European Heart Journal Advance Access originally published online on January 22, 2008
European Heart Journal 2008 29(3):402-412; doi:10.1093/eurheartj/ehm596
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Effect of local heating on restenosis and in-stent neointimal hyperplasia in the atherosclerotic rabbit model: a dose-ranging study
1 Faculté de médecine, Université Paris-Descartes, INSERM U 849, Paris, France
2 Service de cardiologie, CHU Robert Debré, Reims, France
3 Unité d'aide méthodologique, hôpital Maison Blanche, Reims, France
4 Laboratoire de Biochimie, American Memorial Hospital, Reims, France
5 INSERM U 625, Physiologie et pharmacologie vasculaire et rénale, rue de l'école de Médecine, Paris, France
Received 18 October 2006; revised 12 October 2007; accepted 13 November 2007; online publish-ahead-of-print 22 January 2008.
* Corresponding author. service de cardiologie, CHU Robert Debré, Reims, France. Tel: +33 3 26 78 70 20, Fax: +33 3 26 78 41 32. Email: camille.brasselet{at}wanadoo.fr
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Abstract |
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Aims: In-stent restenosis is related to neointimal hyperplasia. Heating reduces neointimal hyperplasia but promotes constrictive remodeling after balloon angioplasty. We aimed to assess the ability of local heating in inhibiting restenosis and in-stent neointimal hyperplasia and its potential side effects on arterial thrombosis.
Methods and results: Atherosclerotic-like lesions were induced in iliac rabbit arteries. One month later, both iliac rabbit arteries were stented. In each animal, one artery was randomized to local heating at four temperatures (50, 60, 80, and 100°C). The contra lateral artery was used as control. Angiographic and histomorphometric analysis were performed 42 days after angioplasty. Immunohistochemistry was performed 3, 15, and 42 days after angioplasty. Angiographic significant reduction of in-stent restenosis after moderate heating (50°C) was related to in-stent neointimal hyperplasia trend to be lower after moderate local heating when compared with controls. In contrast, in-stent thrombosis was similar to controls. Higher temperatures (i.e. 80 and 100°C) also reduced in-stent neointimal hyperplasia but were most frequently associated with severe in-stent thrombosis. Local heating was associated with decreased cell proliferation, collagen density, and increased smooth muscle cell apoptosis and heat shock protein expression.
Conclusion: Moderate heating represents a promising approach to prevent in-stent restenosis via the limitation of the proliferative response without thrombosis induction.
Key Words: Angioplasty • Thrombosis • Heat-shock proteins • Restenosis • Stents
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Introduction |
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Neointimal hyperplasia represents the mechanism of in-stent restenosis. It is related to migration and proliferation of smooth muscle cells (SMCs) and accumulation of extracellular matrix.1–2 Drug-eluting stents (DES) dramatically decreased in-stent restenosis via inhibition of SMC proliferation.3–4 In the pig model, Carter et al. demonstrated that the inhibition of neointimal hyperplasia was obtained at one month by sirolimus-eluting stents. However, at 6 months, the proliferation rate was significantly higher in arteries with sirolimus-eluting stents than controls, suggesting late restenosis.5 Although these experimental data need to be carefully interpreted, the evaluation of major adverse cardiac events in the RAVEL study at 3 years follow-up showed a decrease of the initial benefit. Moreover, delayed restenosis and thrombosis have been recently reported with DES.6–9 This justifies the evaluation of alternate technologies to limit in-stent neointimal hyperplasia without increasing thrombosis. Recently, it has been demonstrated that whole body hyperthermia decreases neointimal hyperplasia in an atherosclerotic rat model.10 Local heating has been also previously evaluated after balloon angioplasty in human without stent. Local heating reduced neointimal hyperplasia but promoted constrictive remodeling and therefore increased restenosis.11–12 In both situations, heating reduced neointimal hyperplasia by increasing SMC apoptosis and decreasing SMC proliferation.13–16 Since stents reduce restenosis by inhibiting constrictive remodeling, we aimed to evaluate the effect of local heating on in-stent restenosis with consideration to subsequent arterial thrombosis using a thermal balloon catheter to investigate a large range of temperatures.
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The investigation conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication No. 85-23, revised 1985). The present study has been approved by the local Institutional Review Board.
Animal model
The study flow chart is summarized in the Figure 1. Focal atherosclerosis was induced in iliac arteries of 56 New Zealand white rabbits by the combination of endothelial abrasion and high cholesterol diet, as previously described.17 Briefly, rabbits were anesthetized by intramuscular injection of xylazine (5 mg/kg) and ketamine (35 mg/kg). After a bilateral femoral artery arteriotomy, a 3F Fogarty embolectomy catheter (Baxter, Deerfield, IL, USA) was used to induce endothelial abrasion in iliac arteries. Local hemostasis was performed by arterial ligatures. Animals were thereafter placed on 2% cholesterol and 6% peanut oil diet during four weeks. Angioplasty was performed 4 weeks later. Conventional balloon angioplasty was first performed in both iliac arteries (one inflation at 6 atm during 60 s with a balloon:artery ratio 1.0–1.2 using equivalent volumes of room temperature water and contrast medium). Then, local heating was randomly applied in one artery at a specific temperature (50, 60, 80, and 100°C) with the PLOSATM> balloon catheter at 2 atm during 60 s (Boston Scientific, Natick, MA, USA). This radiofrequency thermal balloon angioplasty allows controlling both pressure of inflation, duration of inflation and local heating using in situ heated water. The contralateral artery was dilated without local heating and served as control. Bare metal stents (ExpressTM>, Boston Scientific) were implanted in both iliac arteries. Balloon angioplasty and local heating were accurately applied at the exact site of stenting, using similarly length devices. Thereafter, animals were allowed to recover and high cholesterol diet was replaced by normal rabbit chow. Eight out of 56 rabbits died during the study, similarly shared among groups and temperatures (Figure 1). Rabbits were actually included in the present study at the time of sacrifice to avoid discrepancies among groups.
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Angiographic analysis
Minimal luminal diameter (MLD) was defined as the most narrowed site and was blindly measured using electronic calipers before, immediately after and 42 days after angioplasty. The average of two separate measurements determined the final results. Restenosis was defined as the difference between the MLD and the reference diameter normalized by the reference diameter.17
Smooth muscle cell cultures
Human coronary artery SMCs (CASMCs) (Cambrex Corporation, New Jersey, USA) were grown in SmGM medium (Cambrex Corporation). Cells were used at passage 6 in Lab-Tek plates (Nunc A/S, Roskilde, Denmark). The culture medium and a bain-marie were heated as follows (control temperature: 42, 50, 60, 80, and 100°C). The culture medium in the Lab-Tek plates was promptly replaced by suitable preheated culture medium and the Lab-Tek plates were then incubated in the bain-marie maintained at the target temperature during 60 s. The Lab-Tek plates were then removed from the bain-marie and re-incubated. Apoptosis, cell proliferation and heat shock protein 70 (HSP70) expression were assessed by specific antibodies against cleaved-caspase 3 (Cell Signaling Technology), TUNEL (terminal dUTP nick end labeling) (Apoptotag kit, Biogene, Gaitheburg, MD, USA), Ki67 (DAKO, Trappes, France), and HSP70 (Sigma, France), respectively. A negative control was included for each assay. Cleaved-caspase 3, TUNEL, and Ki67 expression were evaluated 24 h after heating, and HSP70 was evaluated 20 h after heating. Apoptosis and cell proliferation were determined as the percentage of immunostained cells. HSP70 expression was assessed as follows: 0 indicated no or barely detectable staining; 1, weak positive staining; 2, moderate limited staining; and 3, strong diffuse staining, as previously described.18
Histomorphometry and immunohistochemistry
Histomorphometry
Forty-two days after angioplasty, animals were killed by an overdose of Pentobarbital. Iliac arteries were removed and placed into processing vials and dehydrated with a graded series of alcohols. They were then infiltrated and embedded in methylmethacrylate plastic. Vials were sealed airtight and placed in a 38°C water bath for polymerization. After polymerization, 1- to 2-mm segments from the proximal, middle, and distal portions of the methacrylate blocks were cut with a diamond-edge rotating precision saw.17 All sections were stained with H&E and red picrosirius.
The lesion site of each artery was defined as the largest neointimal hyperplasia area and was considered for subsequent analyses. Areas were manually identified and measured by computerized-assisted analysis to identify: luminal area, in-stent thrombosis area, residual luminal area, in-stent neointimal hyperplasia, in-stent neointimal thickness, and vessel area (IPS 38; 4.32 software, Alcatel, France). Each parameter was then normalized by the stent area to avoid the discrepancy related to the variation of the stent size.
Collagen density was assessed with picrosirius red at the lesion site, as previously described.19 Collagen content was then obtained as the product of averaged collagen densities and the total in-stent neointimal area, at the same segment.
Cell density was assessed by dividing the number of nuclei by the in-stent neointimal hyperplasia area from two orthogonal segments, at each lesion site.
Immunohistochemistry
Sixty arteries were used for immunohistochemistry analyses 3, 15, and 42 days after angioplasty and local heating. The study flow chart is summarized in the Figure 1. The distribution of the arteries was as follows: four arteries per temperature (control, 50, 60, 80, and 100°C), 3, 15, and 42 days after conventional balloon angioplasty and local heating without stent implantation. In vivo fixation with 10% buffered formaldehyde solution perfused at 100 mmHg for 15 min was realized. Arteries were embedded in paraffin and cut in 5 µm thick sections. Sections were stained with a monoclonal anti-CD31 antibody (dilution: 1:10, DAKO), and a monoclonal anti-rabbit tissue factor (TF) antibody (dilution: 1:30, American Diagnostica, Greenwich, CT, USA) to evaluate re-endothelialization and TF expression, respectively. Re-endothelialization was assessed as the percentage of the luminal CD-31 positive perimeter. In situ detection of apoptotic cells was performed using TUNEL (Apoptotag kit, Biogene), as previously described.20 Finally, cell proliferation and HSP70 expression were assessed as specified above.18 HSP70 and TF were scored as the mean of HSP70 and TF scoring, respectively, as follows: 0 indicated no or barely detectable staining; 1, weak positive staining; 2, moderate limited staining; and 3, strong diffuse staining, as previously described.18
Western blotting for detection of heat shock protein 70 in arteries
Western blotting was assessed as previously described.21 Briefly, arteries at days-3 and -15 after local heating were homogenized by homogenizer in PBS containing 2 mM of a protease inhibitor (i.e. phenylmethylsulfonylfluoride, Sigma). Proteins were separated electrophoretically and transferred to nitrocellulose membranes. Membranes were blocked with 5% nonfat dried milk in Tris-buffered saline and then probed with an anti-HSP70 antibody (Sigma). HSP70 expression according to temperatures was assessed according to arbitrary units, determined as the product of blot area and mean grey pixels of subsequent plots.21
Randomization and statistical analysis
The primary endpoint of the study was to evaluate the impact of local heating on in-stent restenosis assessed by angiography and morphometry. The secondary endpoint of the study was to investigate mechanisms involved in the healing process after local heating (i.e. cell proliferation, apoptosis, and expression of CD31, TF, and HSP70). Rabbits were therefore dedicated to angiographic and morphometric analyses (sacrifice time, day 42) or to immunohistochemistry analyses (sacrifice times, day 3, 15, and 42). The sample size was determined following a preliminary experiment showing that heating had a very strong effect leading to a quasi control of angiographic restenosis. Using the software of Asquang advisor, we calculated that anticipating a mean effect of 5% restenosis in the heated arteries and a 50% restenosis in the control group; considering a number of 16 rabbits in the whole experiment, we had a 77% power to detect this difference.
Animals were first dedicated to both angiography and morphometry analyses. To avoid an order effect, a randomization list has been pre-established using the random function of the Excel software. The operator was kept unaware of the randomization list. Arteries were treated by angioplasty, local heating, and stent implantation, and contralateral artery served as control. Animals were included in the study at the time of sacrifice. In case of pre-mature death, a new identical rabbit replaced it. The purpose of the present study was to take into account a ‘rabbit effect’. For angiographic and morphometric comparisons, assessment of differences between heating and control were first performed using a Kruskal–Wallis one-way analysis of variance by ranks. If this test was significant, a Wilcoxon signed-rank test for paired data for each temperature level was performed. In this analysis, each rabbit therefore gives only one data point.
In rabbits dedicated to immunohistochemistry analyses (i.e. day 3, 15, and 42), bilateral local heating was applied according to a pre-established randomization list. Immunohistochemistry data were analysed as a ranging-dose effect analysis. Comparisons of cell density, cell proliferation, apoptosis, re-endothelialization, and expression of TF at day 3, 15, and 42 among groups were performed according to the ordinal nature of temperatures using a Mann–Kendall trend-test. Similarly, in vivo cell proliferation and HSP70 expression were compared according to the ordinal nature of temperatures using a Mann–Kendall trend-test. Correlations between pairs of factors were evaluated by a Spearman's rank correlation.
All the variables were analysed in a blinded fashion. All the results are expressed as median [min–max]. Differences were considered as significant when P < 0.05.
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In vitro analysis
Cell proliferation was inversely related to local heating since the more the heated arteries, the less the cell proliferation assessed by Ki67 expression (51.6% [44.8–56.8] vs. 37.5% [23.1–40.2] vs. 25.9% [23.2–29.9]; P = 0.029 for controls, 50 and 60°C, respectively). Local heating was related to HSP70 expression since the more the heated arteries, the more the increased HSP70 expression (1.0% [1.0–2.0] vs. 2.0% [1.0–3.0] vs. 3.0% [2.0–3.0]; P = 0.038 for controls, 50 and 60°C, respectively). Similarly, apoptosis was related to local heating (4.7% [2.4–6.4] vs. 21.7% [14.8–28.7] vs. 32.8% [30.4–40.2]; P < 0.001 and 6.1% [3.1–8.4] vs. 29.3% [20.7–30.2] vs. 39.2% [35.9–41.1]; P < 0.001 for controls, 50 and 60°C assessed by cleaved-caspase 3 and TUNEL immunostaining, respectively) (Figure 2). At 80 and 100°C, cells died and detached acutely from the Lab-Tek, avoiding further immunostainings.
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Angiographic analysis
Angiographic analysis is summarized in Table 1. Minimal lumen diameters were similar in each group before and immediately after angioplasty. Forty-two days after angioplasty, 50°C heating resulted in the largest MLD (3.44 mm [2.86–3.71] vs. 1.80 mm [1.43–2.62]; P = 0.043), when compared with control. Indeed, 50°C heating resulted in the lowest restenosis percentage (4.35% [–2.87–10.63] vs. 34.39% [26.84–56.59]; P = 0.043), when compared with control (Figure 3).
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Both MLDs and restenosis percentages were not statistically different among the other groups at 42 days follow-up, when compared with controls. Angiographic restenosis was mainly diffuse in-stent restenosis, without patterns for edge effects.
In-stent neointimal hyperplasia and local heating
Histomorphometry
Histomorphometric analysis is summarized in Table 1. In-stent neointimal area and thickness trended to be lower after 50 and 100°C local heating, when compared with controls (P = 0.068 for both comparisons). Moreover, in-stent collagen densities trended to be lower after 50, 60, and 100°C local heating, when compared with controls (P = 0.068 for both comparisons) (Table 1 and Figure 4). Similarly to angiographic findings, no edge effect was present in controls, 50, 60, 80, or 100°C heated arteries.
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Cell proliferation, apoptosis, and cell density
Results are summarized in Table 2 and in Figure 5. In vivo cell proliferation was inversely related to the extent of heating 3 days after angioplasty. In contrast, cell proliferation was not statistically different among groups at days-15 and -42.
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Apoptosis increased 3 days after local heating in all groups when compared with controls. Apoptosis after 50°C local heating was similar to controls at day 15, whereas it remained increased at higher temperatures.
Cell density was inversely related with the extent of heating and was decreased 15 and 42 days after angioplasty and heating.
Heat shock protein 70 expression
HSP70 expression increased with the level of heating (Table 2). This effect was not sustained since HSP70 expressions were similar among different groups at day 42 (Table 2). HSP70 expression inversely correlated with cell proliferation and positively correlated with the severity of apoptosis (Figure 6). Moreover, HSP70 expression was related to increased local heating, especially after severe local heating (i.e. 80 and 100°C), as assessed by western blotting for detection of HSP70 (Figure 7).
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Thrombosis and local heating
Histomorphometry
In-stent thrombosis was related to the extent of heating. In-stent thrombosis was similar to controls at 50 and 60°C. In contrast, severe heating (80 and 100°C) was associated with a dramatic increase of in-stent thrombosis (Table 1), thus participating mainly to the late loss in such groups (Figure 4). Localization of thrombosis was mainly diffuse without increased thrombosis of stent edges.
Re-endothelialization and tissue factor expression
Fifteen and 42 days after angioplasty, re-endothelialization remained dramatically low in 80 and 100°C groups, whereas it was similarly restored in others (Table 2 and Figure 5).
Three days after angioplasty, TF expression increased after heating. At day 15, TF expression remained sustained after severe heating (80 and 100°C) (Table 2 and Figure 5).
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Discussion |
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The aim of the present study was to evaluate the effect of local heating on neointimal hyperplasia after stent angioplasty in the atherosclerotic rabbit model. We found that moderate heating (i.e. 50°C) inhibited in-stent restenosis and neointimal hyperplasia. In contrast, severe heating (i.e. 80 and 100°C) induced stent thrombosis.
Heating and neointimal hyperplasia
When compared with control, 50°C significantly reduced restenosis and was related to lowered in-stent neointimal hyperplasia, without increasing in-stent thrombosis. In contrast, higher temperatures (80 and 100°C) also reduced neointimal hyperplasia but increased in-stent thrombosis.
In the present study, the reduction of neointimal hyperplasia was associated with a reduction of cell proliferation, collagen accumulation, and increased apoptosis.22–23 The lack of statistically significant difference between in-stent neointimal area and thickness between arteries after moderate local heating and controls can be explained by the low n-value.
We hypothesized that the beneficial effects of heating were related to HSP70 overexpression. Indeed, HSP70 expression increased after heating, correlated with apoptosis and inversely correlated with cell proliferation.
HSPs are known to play an important role in the control of cell density in various conditions of injury, namely after heating.24–25 They clearly reduce cell proliferation in various conditions of experiments.13,15,16 The effect of HSPs on apoptosis is less clear, since it has been reported that HSPs promote or reduce apoptosis.12,26–28 These complex properties might explain the non linear response after local heating in terms of neointimal hyperplasia, cell density, or collagen density among the different groups (i.e. 50 and 60°C), within similar groups or same arteries. We confirmed that heating increased HSP70 expression.25 Moreover, the magnitude of local heating correlated with the extent of apoptosis.
Interestingly, we observed that heating reduced collagen accumulation. The accumulation of the extracellular matrix after arterial injury is known to appear after cell proliferation.19 The difference in collagen contents at day 42 can be therefore interpreted as the consequence of decreased cell densities.29
Heating and in-stent thrombosis
Thrombosis is a major concern in the field of interventional cardiology. Moderate heating did not increase thrombosis. In contrast, thrombosis was dramatically increased after severe heating. Interestingly, similar deleterious effect of heating has been previously related with high temperatures.12,30 Fifteen and 42 days after angioplasty, re-endothelialization was similar between control and moderately heated arteries, whereas re-endothelialization remained incomplete after severe heating. This deleterious effect of severe heating on the endothelial regrowth process is closely similar to those obtained with intra coronary brachytherapy. Experimental and clinical evaluations have already shown that delayed re-endothelialization was associated with thrombosis.20,31
TF is acutely overexpressed after vascular injury, but its expression returns to baseline within the first days.32 Interestingly, its expression remained at a high level after severe heating 15 days after injury. Thus, sustained expression of TF in both 80 and 100°C might be related to the effect of local high heating. Interestingly, Fram et al.30 reported that severe heating (70°C) was associated with significant increase in intra arterial thrombus formation.
Thus, delayed re-endothelialization and a sustained expression of TF may both explain in-stent thrombosis after severe heating.
Limitations of the study
The results observed in this animal model may not reflect all the pathological mechanisms occurring in humans, even if we used an atherosclerotic stented rabbit model. Further studies are warranted to confirm the results and further refine the optimal temperature ranges.
In conclusion, our findings suggest that moderate local heating has a favorable effect on the combination of healing process and thrombosis formation after balloon angioplasty plus stent implantation in a rabbit atherosclerotic model. Owing to its simplicity, this complementary technique appears as clinically relevant and feasible.
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This study was supported by a grant from Boston Scientific Corporation.
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We thank Eric Simso for carefully reviewing the manuscript; Evelyne Colomb, Gérard Pivert, and Martine Douheret for their help in the histology preparation.
Conflict of interest: none declared.
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References |
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