Angiotensin II type 1 receptor blockers suppress neointimal hyperplasia after stent implantation in carotid arteries of hypercholesterolemic rabbits Naoki Ichikawa1, Naoki Toma1, Fumihiro Kawakita1, Satoshi Matsushima1, Kyoko Imanaka-Yoshida2,3, Toshimichi Yoshida2,3, Waro Taki1, Hidenori Suzuki1,3 1

Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan, 2Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan, 3Research Center for Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan

Objectives: The purpose of this study was to examine whether oral administration of an angiotensin II type 1 receptor blocker (ARB) inhibited in-stent neointimal hyperplasia in carotid arteries of hypercholesterolemic rabbits. Methods: Eleven male New Zealand white rabbits were subjected to endothelial injuries of the right common carotid arteries using a balloon catheter and then received chow containing 1% cholesterol for 6 weeks. A balloon-expandable stainless steel stent was subsequently inserted at the injured sites of the arteries. After stenting, five rabbits were randomly treated with an oral ARB, candesartan cilexetil (5 mg/kg per day orally), while the remaining six rabbits acted as untreated controls. Four weeks after the implantation, the rabbits were killed, followed by collection of the arteries including the stents. After careful removal of the stents, tissue sections were prepared and analyzed by morphometric and immunohistochemical methods. Results: The mean thickness of the neointima was 53.6¡17.0 mm in the ARB-treated group, which was significantly reduced compared to 95.9¡16.7 mm in the control group (P50.0012). Immunohistochemistry showed a decrease in accumulation of macrophages and tenascin-C expression in the arterial wall in the ARB-treated animals. Discussion: This study suggested that systemic administration of an ARB suppressed neointimal hyperplasia in the carotid artery following stent implantation by the anti-inflammatory effects, although the animal cohort tested was rather small. This finding implies that ARBs may be useful and practical agents for protection against in-stent restenosis in humans, and warrants further basic and clinical studies. Keywords: Angiotensin II, Angiotensin II type 1 receptor blocker, Carotid artery, Macrophage, Neointimal hyperplasia, Stent

Introduction Stenting of carotid arteries has emerged as an alternative to endarterectomy for the treatment of carotid artery diseases.1 This procedure has become safe, with a high success rate, following the introduction of protection devices, which prevent distal embolisms, although in-stent restenosis is still a major clinical issue after stenting, and occurs in 4% to 8% of cases.2,3 Several cellular and molecular events may develop sequentially after vascular injury caused by balloon Correspondence to: N. Ichikawa, Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 5148507, Japan. Email: [email protected]. jp

ß W. S. Maney & Son Ltd 2015 DOI 10.1179/1743132814Y.0000000436

angioplasty and stenting.4,5 These include elastic recoil, thrombus, and neointimal formation, and the constrictive remodeling of the arterial wall ultimately leads to restenosis.4 In contrast to balloon angioplasty, a major cause of in-stent restenosis is neointimal hyperplasia, as a result of the implanted stent preventing both vascular recoil and adverse remodeling of the arterial wall.5 Angiotensin II is an important factor in the inflammatory response and also the proliferation of vascular smooth muscle cells (VSMCs) in the vessel wall.6,7 These events are induced by angiotensin II binding to the angiotensin II type 1 (AT1) receptor.6,7 However, effects of an AT1 receptor blocker (ARB)

Neurological Research

2015

VOL .

37

NO .

2

147

Ichikawa et al.

AT1 receptor blockers suppress neointimal hyperplasia

on in-stent restenosis have been controversial. The valsartan for prevention of restenosis (Val-PREST) trial showed that chronic administration of the ARB reduced the rate of in-stent restenosis after stenting of coronary lesions,8 while other clinical trials with ARBs have shown no effects on in-stent restenosis in coronary arteries.9 Another ARB, candesartan cilexetil, also did not reduce neointimal formation in the stented rat abdominal aorta.10 In contrast, candesartan cilexetil inhibited neointimal formation after balloon-injured carotid artery in both dogs and rats,11,12 although no studies have examined if an ARB prevents post-stenting restenosis or neointimal hyperplasia in carotid arteries in an animal model. Considering the discrepancy between animal researches and clinical trials, we hypothesized that ARB’s effects against in-stent neointimal hyperplasia may be different among aorta, coronary and carotid arteries or depending on the predominant etiology of the disease. In the present study, we evaluated whether an ARB, candesartan cilexetil, prevented in-stent restenosis following stent implantation in the carotid artery of hypercholesterolemic rabbits. In addition, we examined the local pathological changes in the stented arteries.

Materials and Methods Animals The experiments were performed in accordance with the guideline for animal experiments in our institute. Eleven adult, male, New Zealand white rabbits weighing 3.0–3.5 kg (SLC, Hamamatsu, Japan) were used in the study. All rabbits were anesthetized by an intramuscular injection of ketamine hydrochloride (50 mg/kg body weight) and an intravenous injection of sodium pentobarbital (25 mg/kg body weight). Under local anesthesia induced by a subcutaneous injection of lidocaine, the right femoral artery was exposed to allow insertion of a no. 5 French sheath introducer. The right common carotid artery was then injured by introducing a 3.0 mm silicone balloon catheter through the right femoral artery, by means of inflation and withdrawal of the balloon back through the common carotid artery. This procedure denuded the endothelium and was repeated for a total of three passes through the artery at the level of the C3 and C4 vertebral bodies. All rabbits were then fed a diet containing 1% cholesterol for 6 weeks from the day of balloon injury with the aim of inducing atherosclerotic lesions.

Stent implantation After 6 weeks, a balloon-expandable stainless steel stent (ACS RX Multi-link plusH; Guidant, Temecula, CA, USA) was deployed at the site of balloon injury in the right common carotid artery of all rabbits. The stents were 3 mm in diameter and 15 mm in length

148

Neurological Research

2015

VOL .

37

NO .

2

when expanded. Angiography was performed before and immediately after stent implantation to confirm the location of the stents. At the time of stent implantation, 100 IU/kg of heparin was injected intravenously. No other anticoagulant or antiplatelet agents were administered either before or after stent deployment. The rabbits were divided randomly into two groups, an ARB-treated group and an untreated control group. Five rabbits were treated with oral administration of an ARB, candesartan cilexetil (Takeda Chemical Industries, Osaka, Japan) at a dose of 5 mg/kg daily for 4 weeks from the day of stenting until death. The remaining six rabbits received no treatment. The dose of candesartan was selected based on the results of earlier studies that the drug prevented neointimal proliferation after balloon injury in carotid arteries.11,12 After stent implantation, all rabbits in both groups received regular diets of chow instead of the chow supplemented with 1% cholesterol.

Animal killing and tissue preparation The rabbits were killed at 28 days after the stent implantation by a lethal dose of sodium pentobarbital anesthesia (100 mg/kg body weight) after blood pressure was measured by a cuff placed around the left foreleg. The stented segments of the right common carotid arteries were then isolated surgically with vascular clamps applied above and below the implants. The isolated segments were then perfused with normal saline to wash blood out, and excised en bloc, followed by the specimens containing stents being fixed overnight in a buffered solution containing 3.7% formaldehyde. The common carotid artery containing the stent was cut and opened longitudinally, and then divided into 5 mm-transverse segments using scissors. The stent struts were carefully removed from the surface of the segments using microforceps under a stereomicroscope. The samples were dehydrated and embedded in paraffin, followed by the preparation of 4 mm sections. After dewaxing and rehydration, the sections were stained with hematoxylin and eosin (HE) or Elastica van Gieson.

Morphometric analyses Morphometric analyses were carried out on cross sections of each artery stained with Elastica van Gieson. Neointimal thickness was measured blindly using the image analysis software, Scion image (Scion Corporation, Frederick, MD, USA). Neointimal thickness at the midpoint between the struts was randomly measured on five cross-sections of an individual artery. The mean measurements of the individual arteries were then calculated and compared between the treated and control groups. All data were expressed as mean¡standard deviation. After confirming that each population being compared followed

Ichikawa et al.

AT1 receptor blockers suppress neointimal hyperplasia

Figure 1 Blood pressure at 28 days after stent implantation. There are no significant differences in systolic or diastolic blood pressure between the control and ARB-treated groups. SBP, systolic blood pressure; DBP, diastolic blood pressure.

a normal distribution using Shapiro–Wilk W tests, the unpaired, two-tailed Student’s t-test was used to compare the data of the two groups, with a P value of (0.05 being considered as statistically significant.

Immunohistochemistry on paraffin-embedded sections Immunohistochemical staining was carried out to identify macrophages and VSMCs. The sections were treated with the monoclonal antibodies, RAM11 (Dako, Kyoto, Japan) and anti-alpha-smooth muscle actin (alpha-SMA; Dako) antibodies, followed by the labeled streptavidin-biotin (LSAB) technique. The sections were also incubated with the monoclonal anti-tenascin-C (TNC, a matricellular protein; Immuno-Biological Laboratories, Takasaki, Japan) antibody, followed by the LSAB technique, and were counterstained with HE solution for light microscopic examination. Negative controls consisted of serial sections incubated with buffer alone instead of the primary antibodies.

Figure 2 Rabbit common carotid artery at 28 days after stent implantation in the control (a) and the ARB-treated (b) groups (Elastica van Gieson’s stain; magnification, 6200). The stent struts were removed gently after fixation. The neointimal thickness of the rabbit common carotid arteries was measured at the midpoint between the struts (lines in a and b).

(53.6¡17.0 mm) was significantly reduced compared with the control group (95.9¡16.7 mm, P50.0012; Fig. 3).

Immunohistological findings In both the treated and control groups, cells positive for alpha-SMA were densely present in all layers of the artery (Fig. 4). A large number of RAM11positive macrophages were accumulated in the neointimal and outer smooth muscle cell layers of

Results Blood pressure The blood pressure data were summarized in Fig. 1, which showed that treatment with candesartan cilexetil (5 mg/kg daily) had no significant effect on either systolic (SBP) or diastolic blood pressure (DBP), compared with the control group (SBP, 167¡32 versus 161¡20 mmHg; DBP, 97¡34 versus 111¡14 mmHg in the ARB-treated and control groups, respectively).

Morphometric analyses At 28 days after the stent implantation, concentric thickening of the intimal layer was observed in both groups (Fig. 2). However, the thickness of in-stent neointimal hyperplasia in the ARB-treated group

Figure 3 Neointimal thickness of stented rabbit common carotid arteries. P value, unpaired t-test.

Neurological Research

2015

VOL .

37

NO .

2

149

Ichikawa et al.

AT1 receptor blockers suppress neointimal hyperplasia

Figure 4 Immunohistochemical staining for alpha-SMA in rabbit common carotid arteries at 28 days after stent implantation in the control (a) and the ARB-treated (b) groups (magnification, 6200).

Figure 6 Immunohistochemical staining for TNC in rabbit common carotid arteries at 28 days after stent implantation in the control (a) and the ARB-treated (b) groups (magnification, 6200).

the control animals (Fig. 5a). In contrast, in the ARB-treated group, much fewer infiltrations of macrophages were observed and the area was limited to the neointimal layer between the stent struts (Fig. 5b). The immunostaining of TNC was observed

in the limited area around the stent struts in the control group, but not in the ARB-treated group (Fig. 6).

Figure 5 Immunohistochemical staining for RAM11 in rabbit common carotid arteries at 28 days after stent implantation in the control (a) and the ARB-treated (b) groups (magnification, 6200).

150

Neurological Research

2015

VOL .

37

NO .

2

Discussion In the present study, an ARB, candesartan cilexetil, prevented in-stent neointimal hyperplasia following stent implantation in the carotid artery of hypercholesterolemic rabbits, associated with a decrease in infiltrations of macrophages and tenascin-C expression in the arterial wall. These findings first showed that the ARB may suppress in-stent restenosis after carotid artery stenting by the anti-inflammatory effects. Previous studies on stented coronary arteries in animal models as well as a small number of clinical cases have provided insights into the mechanisms of restenosis that occurs after balloon angioplasty and stenting.4,13 In contrast with balloon angioplasty, restenosis after stenting is due principally to neointimal formation rather than elastic recoil and constrictive remodeling.4 A previous study using coronary arteries of swine demonstrated that macrophages were observed around stent struts in stented animals after 28 days, whereas these changes were not seen in animals with balloon injuries but without stenting.4 In humans, tissue obtained from coronary arteries after stenting showed medial disruption, penetration of the lipid core in atherosclerotic arteries and increased numbers of inflammatory cells including macrophages associated with stent struts.13 These

Ichikawa et al.

findings suggest that inflammation has a role in restenosis and a possible relationship between vascular changes and atherosclerotic plaque in coronary arteries. In regard of stented carotid artery, there are few available data, but an autopsy case showed neointimal hyperplasia and macrophage infiltration around the stent struts.14 The animal model used in our study involved feeding a diet containing 1% cholesterol to rabbits with balloon-induced endothelial cell injury. This resulted in marked neointimal thickening at the site of the stents, similar to that seen in the human coronary and carotid arteries following stenting.13,14 Arterial samples from our control group of animals showed that numerous macrophages infiltrated into the arterial walls, especially around the stent struts. In this study, thus, the combination of endothelial cell injury and the 6-week diet supplemented with 1% cholesterol caused in-stent restenosis in the atherosclerotic carotid arteries, reproducing the situation seen in human cases of stented carotid arteries. We also demonstrated that AT1 receptor blockade with candesartan cilexetil resulted in a reduction in neointimal thickening and suppression of macrophage accumulation in the intima and media layers independent of blood pressure changes. It is well known that angiotensin II is an important factor causing proliferation of VSMCs in the arterial wall6 in addition to stimulating production of intercellular adhesion molecule-1, chemokine monocyte chemotactic protein-1, and the cytokine interleukin-6 in these cells.7,13,15 TNC, a matricellular protein, is also induced by inflammation16,17 and angiotensin II,18 while TNC itself can induce inflammatory reactions.16 Many reports have documented up-regulation of TNC in myofibroblasts or activated VSMCs in injured systemic arteries, which regulates cell phenotype and promotes the proliferation of VSMCs and deposition of extracellular matrix.16,19 In catheter-injured rat carotid arteries, adventitial myofibroblasts expressed TNC and migrated across the vascular wall toward the lumen, causing neointimal formation.19 In TNC-null mice, however, much less neointimal hyperplasia was seen than in wild-type mice at the arterial anastomotic site of a simple aortotomy model.20 ARB administration, thus, may have the ability to suppress both VSMC proliferation and inflammatory responses via TNC-related and unrelated mechanisms, resulting in a significant decrease of neointimal formation, although TNC was expressed only in the neointima around the stent struts and therefore the role might be limited in this study, as well as a clinical pilot study using valsartan.21 As a consequence of these actions, ARB may improve long-term durability and safety of stents in patients with carotid artery disease.

AT1 receptor blockers suppress neointimal hyperplasia

Angiotensin II is generated from angiotensin I by two different enzymes, angiotensin converting enzyme (ACE) and chymase.22 Although ACE inhibitors have been shown experimentally to prevent restenosis after balloon injury in carotid arteries,23 randomized trials with ACE inhibitors failed to demonstrate any reduction in the prevalence of restenosis after conventional balloon angioplasty of coronary lesions.24 The ability of human blood vessels to produce angiotensin II is dependent on chymase in approximately 60%, and on ACE in 30– 40%.22 Therefore, ACE inhibition alone is not able to completely block the angiotensin II forming pathway. In contrast, ARBs theoretically block the function of angiotensin II completely by inhibiting the activity of the AT1 receptor. The Val-PREST trial randomly compared the effect of oral administration of valsartan on angiographic in-stent restenosis after coronary artery stenting with the placebo treatment in 200 patients.8 The study reported a significantly lower incidence of restenosis in the valsartan-treated group (19%) compared with the placebo treatment group (39%), 68% of whom received ACE inhibitors. There is now widespread and increasing use of carotid artery stenting as an alternative to endarterectomy for the treatment of carotid artery diseases.1,3 Also, stenting for intracranial atherosclerotic stenosis has become possible after the introduction of flexible coronary stents.25 With the development of more flexible stents, treatment of stenosis in smaller arteries will become possible, although in-stent restenosis must remain a concern in the stenting of small intracranial arteries. Our study suggests that oral administration of ARBs may prevent in-stent restenosis that occurs after stenting of atherosclerotic stenosis in such vessels. This study is somewhat limited, in that the number of animals was limited. In addition, it remains undetermined if suppressed inflammatory reactions observed in this study were a cause or a result of decreased neointimal hyperplasia. Thus, further studies are necessary to confirm the ARB’s effects basically as well as clinically.

Conclusions We investigated whether angiotensin II type I receptor blockade prevented neointimal hyperplasia following stent implantation in carotid arteries of hypercholesterolemic rabbits. Oral ARB treatment was associated with a significant reduction in neointimal thickness at 28 days after the stent implantation, although the animal cohort tested was rather small. Neointima in ARB-treated animals also seemed a marked decrease in the number of infiltrating macrophages and the TNC expression, compared to control animals. Taken together, these findings

Neurological Research

2015

VOL .

37

NO .

2

151

Ichikawa et al.

AT1 receptor blockers suppress neointimal hyperplasia

suggest that ARB administration may suppress neointimal formation in the stented carotid arteries possibly by inhibiting inflammatory reaction, warranting further basic and clinical studies.

9

10

Disclaimer Statements Contributors We thank Mr Taku Takeuchi (Department of Neurosurgery, Mie University Graduate School of Medicine) for his technical assistance. This study was supported in part by a grant-in-aid for Scientific Research from Mie Foundation for the Promotion of Science to Dr Toma and Japan Society for the Promot ion of Science to Dr Suzuki.

11

12

13

Funding Japan Society for the Promotion of Science. Conflicts of interest The authors report no conflicts of interest.

14

Ethics approval The experiments were performed in accordance with the guideline for animal experiments in our institute.

15

References

16

1 Brott TG, Halperin JL, Abbara S, Bacharach JM, Barr JD, Bush RL, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS Guideline on the Management of Patients With Extracranial Carotid and Vertebral Artery Disease: Executive Summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. J Am Coll Cardiol. 2011;57:1002–44. 2 Chakhtoura EY, Hobson RW 2nd, Goldstein J, Simonian GT, Lal BK, Haser PB, et al. In-stent restenosis after carotid angioplastystenting: incidence and management. J Vasc Surg. 2001;33:220–5. 3 Yadav JS, Roubin GS, Iyer S, Vitek J, King P, Jordan WD, et al. Elective stenting of the extracranial carotid arteries. Circulation. 1997;95:376–81. 4 Nakatani M, Takeyama Y, Shibata M, Yorozuya M, Suzuki H, Koba S, et al. Mechanisms of restenosis after coronary intervention. Difference between plain old balloon angioplasty and stenting. Cardiovasc Pathol. 2003;12:40–8. 5 Hoffmann R, Mintz GS, Dussaillant GR, Popma JJ, Pichard AD, Satler LF. Patterns and mechanisms of in-stent restenosis. Circulation. 1996;94:1247–54. 6 Daemen MJ, Lombardi DM, Bosman FT, Schwartz SM. Angiotensin II induces smooth muscle cell proliferation in the normal and injured rat arterial wall. Circ Res. 1991;68:450–6. 7 Hernandez-Presa M, Bustos C, Ortego M, Tunon J, Renedo G, Ruiz-Ortega M, et al. Angiotensin-converting enzyme inhibition prevents arterial nuclear factor-kappa B activation, monocyte chemoattractant protein-1 expression, and macrophage infiltration in a rabbit model of early accelerated atherosclerosis. Circulation. 1997;95:1532–41. 8 Peters S, Gotting B, Trummel M, Rust H, Brattstrom A. Valsartan for prevention of restenosis after stenting of type B2/

152

Neurological Research

2015

VOL .

37

NO .

2

17

18 19

20

21

22

23

24

25

C lesions: the Val-PREST trial. J Invasive Cardiol. 2001;13:93– 7. Kun X, Yong L, Bo J, Hai-Ming S. Neointimal hyperplasia inhibition effect of angiotensin II type 1 receptor blockers in patients after coronary stent implantation: a meta-analysis. Am J Cardiovasc Drugs. 2011;11:209–13. Groenewegen HC, van der Harst P, Roks AJ, Buikema H, Zijlstra F, van Gilst WH, et al. Effects of angiotensin II and angiotensin II type 1 receptor blockade on neointimal formation after stent implantation. Int J Cardiol. 2008;126:209–15. Miyazaki M, Shiota N, Sakonjo H, Takai S. Angiotensin II type 1 receptor antagonist, TCV-116, prevents neointima formation in injured arteries in the dog. Jpn J Pharmacol. 1999;79:455–60. Taguchi J, Abe J, Ohno M, Schwartz SM, Kurokawa K. Topical application of AT1 receptor antagonists prevents medial and neointimal proliferation after balloon injury. Blood Press Suppl. 1994;5:38–42. Grewe PH, Deneke T, Machraoui A, Barmeyer J, Muller KM. Acute and chronic tissue response to coronary stent implantation: Pathologic findings in human specimen. J Am Coll Cardiol. 2000;35:157–63. Toma N, Matsushima S, Murao K, Kawafuchi K, ImanakaYshida K, Yoshida T, et al. Histopathological findings in a human carotid artery after stent implantation. Case report. J Neurosurg. 2003;98:199–204. Pastore L, Tessitore A, Martinotti S, Tniato E, Bravi MC, Ferri C, et al. Angiotensin II stimulates intercellular adhesion molecule-1 (ICAM-1) expression by human vascular endothelial cells and increases soluble ICAM-1 release in vivo. Circulation. 1999;100:1646–52. Chiquet-Ehrismann R, Chiquet M. Tenascins: regulation and putative functions during pathological stress. J Pathol. 2003;200:488–99. Shiba M, Fujimoto M, Imanaka-Yoshida K, Yoshida T, Taki W, Suzuki H. Tenascin-C causes neuronal apoptosis after subarachnoid hemorrhage in rats. Transl Stroke Res. 2014;5:238–47. Ma S, Yang D, Li D, Tang B, Sun M, Yang Y. Cardiac extracellular matrix tenascin-C deposition during fibronectin degradation. Biochem Biophys Res Commun. 2011;409:321–7. Wallner K, Sharifi BG, Shah PK, Noguchi S, DeLeon H, Wilcox JN. Adventitial remodeling after angioplasty is associated with expression of tenascin mRNA by adventitial myofibroblasts. J Am Coll Cardiol. 2001;37:655–61. Yamamoto K, Onoda K, Sawada Y, Fujinaga K, ImanakaYoshida K, Shimpo H, et al. Tenascin-C is an essential factor for neointimal hyperplasia after aortotomy in mice. Cardiovasc Res. 2005;65:737–42. Suzuki H, Sano T, Umeda Y, Yamamoto A, Toma N, Sakaida H, et al. Valsartan prevents neointimal hyperplasia after carotid artery stenting by suppressing endothelial cell injuries. Neurol Res. 2015;37:35–42. Okunishi H, Oka Y, Shiota N, Kawamoto T, Song K, Miyazaki M. Marked species difference in the vascular angiotensin IIforming pathway: human versus rodents. Jpn J Pharmacol. 1993;62:207–10. Powell JS, Clozel JP, Muller RK, Kuhn H, Hefti F, Hosanq M, et al. Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Science. 1989;245:186–8. Faxon DP. Effect of high dose angiotensin-converting enzyme inhibition on restenosis: final results of the MARCATOR Study, a multicenter, double-blind, placebo-controlled trial of cilazapril. The Multicenter American Research Trial with Cilazapril after Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MARCATOR) Study Group. J Am Coll Cardiol. 1995;25:362–9. Terada T, Tsuura M, Matsumoto H, Masuo O, Tsumoto T, Yamaga H, et al. Endovascular therapy for stenosis of the petrous or cavernous portion of the internal carotid artery: percutaneous transluminal angioplasty compared with stent placement. J Neurosurg. 2003;98:491–7.

Angiotensin II type 1 receptor blockers suppress neointimal hyperplasia after stent implantation in carotid arteries of hypercholesterolemic rabbits.

The purpose of this study was to examine whether oral administration of an angiotensin II type 1 receptor blocker (ARB) inhibited in-stent neointimal ...
339KB Sizes 4 Downloads 4 Views