Protocols Tissue kallikrein preventing the restenosis after stenting of symptomatic MCA atherosclerotic stenosis (KPRASS) Wenya Lan1†, Fang Yang1†, Ling Liu1†, Qin Yin1, Min Li1, Zhuangli Li1, Hongfei Sang1, Gelin Xu1, Minmin Ma1, Zhizhong Zhang1, Zhenguo Liu2, Xinfeng Liu1*, and Renliang Zhang1,2* Rationale Many recent studies suggest that the kallikreinkinin system play a protective role in the impairment of vascular smooth muscle cells and vascular endothelial cell. Aims The study aims to determine whether tissue kallikrein is efficacy for preventing the long-term in-stent restenosis after stenting of symptomatic atherosclerotic stenosis of the middle cerebral artery M1 segment. Design This is a Phase II, randomized, single-blinded, controlled trial. In line with SAMMPRIS stenting indications, patients (n = 90) with the symptomatic the middle cerebral artery M1 segment stenosis ≥70% and successfully treated with stent will be enrolled. Eligible patients will be randomized using computer generated numbers, and allocated to receive tissue kallikrein treatment or not. Patients in tissue kallikrein treatment group will be prescribed with intravenous infusion of tissue kallikrein (0·15 PNAU/d, dissolved in 100 ml saline) for 7 days after stenting and then oral administration of pancreatic kallikrein enteric-coated tablet (240 U, 3/d) to the end of study. As the foundation treatment, all the enrolled patients will receive aspirin (100 mg/d), clopidogrel (75 mg/d), and atorvastatin (20 mg/d) for the first 6 months and continue with the combination of aspirin and atorvastatin at the previous dosage. Study outcomes Patients will be evaluated at 1, 6 and 12 months after stenting. The primary outcomes are the in-stent restenosis rate, new stroke or aggravation of the previous ischemic stroke ipsilateral to the severe stenotic artery. Secondary outcomes include stroke of other artery territories, myocardial infarction and vascular death. Modification of stroke knowledge, exercise and diet habit, smoking cessation and available laboratory data will also be recorded. Conclusion As our pilot study, tissue kallikrein would be expected to prevent the long-term in-stent restenosis after stenting of the symptomatic middle cerebral artery dramatically. Key words: atherosclerotic stenosis, in-stent restenosis, ischemic stroke, the middle cerebral artery, tissue kallikrein
Correspondence: Xinfeng Liu* and Renliang Zhang*, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, China. E-mail: [email protected]; [email protected] 1 Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China 2 Davis Heart & Lung Research Institute, Ohio State University Medical Center, Columbus, OH, USA Received: 25 June 2013; Accepted: 10 October 2013; Published online 20 December 2013 †
These authors contributed equally to this work and share first authorship.
Conflicts of interest: None declared. DOI: 10.1111/ijs.12229 © 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization
Introduction Intracranial atherosclerotic stenosis of the major intracranial arteries is one of the most important risk factors of ischemic stroke, which accounts for 10–15% of all ischemic strokes (1). It is particularly prevalent in Chinese populations, with estimated incidence in stroke populations ranging from 33% to 50% (2). The Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) trial revealed, despite the best antithrombotic therapy, the rate of ischemic stroke in the territory of the high-grade (50–99%) stenotic artery was nearly 12% at 1 year (3), and the stroke rate was up to 18% at 1 year in the subgroup of patients with intracranial stenosis >70% (4). Even more important, strokes ipsilateral to the severe stenotic artery were hemispheric and often disabling (5). For these reasons, people paid more and more attention to percutaneous transluminal angioplasty with stenting (PTAS) for the symptomatic intracranial arterial stenosis intractable to medical therapy (6–9). A major concern for PTAS for the intracranial stenosis has been the incidence of in-stent restenosis (ISR) (10). In our previous studies, the rate of ISR after intracranial stenting with bare metal balloon-mounted stents was about 30% at a median follow-up of 7 months (11), and it seems more frequent with the Selfexpanding stents (8,12). The pathogenesis of ISR remains incompletely understood, maybe mainly due to the proliferation of intima associated with the inflammation after stenting (13,14). At present, there are no definite evidenced-based interventions to prevent ISR after intracranial stenting. A series of studies have confirmed the kallikrein-kinin system (KKS), including kallikrein, kininogen and kinin, plays an important role in the regulation of inflammation secondary to acute and chronic ischemic brain injury (15–17). Emanueli (18) found that hTK gene delivery can inhibit the formation of neointimal induced by the common carotid artery ligation in mice. Further study revealed hTK gene transfection in VSMC lead to increased secretion of TK and inhibition of VSMC proliferation (19). In addition, it was also observed that the serum TK levels were coincident with the carotid artery stenosis (20). The more severe the stenosis is, the higher the serum TK level is, and the serum TK decreased after carotid artery angioplasty and stent placement. These results suggest that KKS play an important regulatory role in vascular remodeling and TK may exert a beneficial infulence in the process of ISR. In this analysis, we hypothesized that the rate of ISR and the frequency of subsequent stroke or other vascular events would be reduced in TK-treated patients after PTAS. Vol 9, June 2014, 533–535
533
Protocols
W. Lan et al.
Table 1 The inclusion/exclusion criteria Inclusion criteria: 1. TIA or stroke in the MCA territory refractory to aggressive anti-platelet and regular statin therapy in 3 months 2. Symptomatic MCA M1 segment stenosis ≥70% confirmed with DSA 3. Successfully treated with PTAS without acute surgical complications in 12 h after operation 4. All patients provided fully informed consent Exclusion Criteria: 1. Using angiotensin-converting enzyme inhibitors (Because angiotensin-converting enzyme inhibitors can inhibit the degradation of kinin caused by kininase II (K II) ) 2. Severe cardiopulmonary dysfunction, chronic liver disease (A/G inversion, ALT increased 2-fold greater than normal), abnormal renal function (serum creatinine greater than 1·5 times normal) 3. Allergies, the history of allergy to multi-drug 4. The history of cerebral hemorrhage, brain tumors, brain trauma, cerebral embolism and other brain lesions 5. During pregnancy or breast-feeding 6. Not expected to complete follow-up
Methods Overview KPRASS is a Phase II, randomized, single-blinded, controlled trial. Patients with the symptomatic MCA M1 segment stenosis ≥70% and successfully treated with PTAS are the source group. The patients are prospectively followed for a minimum of one year and ISR will be evaluated with DSA at 6 and 12 months after PTAS. Patient population Patients with the symptomatic MCA severe stenosis and successfully treated with PTAS are the source group. No racial or gender groups are excluded. Participants are recruited from the inpatient stroke services of the Jinling Hospital, a university-affiliated Grade-A tertiary hospital in Nanjing. The sample consists of adults (age > 30) hospitalized of an ischemic stroke or TIA due to atherogenic cerebrovascular disease. Ischemic stroke is defined as rapidly developing clinical signs of focal disturbance of cerebral function lasting more than 24h. In the case of TIA or clinical stroke without lesions visualized on neuroimaging, a stroke neurologist confirms the diagnosis. Diagnostic evaluation is performed at the discretion of the treating physicians, but commonly including MRA, CT angiography (CTA), TCD and DSA. Patients with evidence of ≥70% MCA M1 segment confirmed with DSA are screened for final eligibility based upon the inclusion/exclusion criteria (Table 1). Randomization and blinding Eligible patients will be randomized by computer generated numbers in sealed opaque envelopes. A detailed neurological evaluation including the standardized assessments (such as NIHSS, Barthel Index etc.) is performed by the blinded study physician. Blinded raters obtain all follow up data. The patients are instructed not to reveal their treatment assignment. Vascular events, re-hospitalizations, and other clinical event are adjudicated by a physician blinded to treatment assignment. Experimental intervention Participants in TK-treatment group will receive intravenous infusions of kallikrein (0·15 PNAU/d, dissolved in 100 ml saline) for 7 days after PTAS and followed with oral administration of Pancre-
534
Vol 9, June 2014, 533–535
atic Kinionogenase Enteric-coated Tab (240U, 3/d) to the end of study. All the patients enrolled will receive aspirin (100 mg/d), clopidogrel (75 mg/d), and atorvastatin (20 mg/d) for the first 6 months and continue with the combination of aspirin and atorvastatin at the previous dosage. Study assessments The nature and frequency of cerebral ischemic events is recorded. Medications at the time of enrollment and specific data regarding vascular risk factors are gathered including age, gender, race, hypertension, diabetes mellitus, lipid disorder, coronary disease, smoking, alcohol consumption, and parental death from stroke. The National Institute of Health Stroke Scale (NIHSS) is administered, and functional status assessed using the Barthel Index (BI), and modified Rankin Scales (mRS). The MRI is applied to confirm the diagnosis and will be rechecked as needed during the follow-up period. Available laboratory data including platelet inhibitory rate by Thrombelastography (TEG) Platelet MappingTM, bradykinin (BK), tissue kallikrein (TK), cGMP, cAMP, high sensitivity C-reactive protein (hs-CRP), TNF-α, IL-6, LDL-Ch and HDL-Ch, casual or fasting plasma glucose is collected, in addition to results of cerebral imaging studies. A standardized DSA and PTAS are performed, and DSA is used to re-evaluate vascular lesion and the ISR at 6 months and 12 months. Selected baseline measurements and study assessments can be found in Table 2. Ethics approval The study has received an approval of the Jinling hospital ethical committee. And this trial is registered in clinicaltrials.gov (NCT01558245). Data management Data quality control includes data checks that are built into this data system to ensure the integrity of all data entered for each study participant. All study imaging data is centrally reviewed to confirm adequate imaging quality and completeness. Initial determination of MCA stenosis for eligibility is made using the WASID technique (21). Relevant angiographic images are reviewed by a blinded neuroradiologist for final determination of degree of stenosis. © 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization
Protocols
W. Lan et al.
Table 2 Study assessments Baseline 1 month 6 months 12 months History and physical NIH Stroke Scale Functional assessments: Barthel Index, Modified Rankin Scale Thrombelastography (TEG) Platelet MappingTM MRI DSA Laboratory data
X X X
X X
X X X X
X
X X
X X
X
X
X X
X X
Sample size To achieve a sample size using Power and sample size program, a 0·05 significance level and 80% power was first calculated. Pilot data was obtained from 10 patients in which the in-stent restenosis rate was 10% in the intervention group, and around 30% in the control group. The sample size required is 90. So, a 10% drop out rate was assumed, and the target for enrollment is 99 participants.
Conclusion The prevention for ISR is of great importance to ischemic stroke patients for reducing recrudescence, disability and improving worse outcomes. KPRASS will determine whether the combination with kallikrein can reduce the incidence of ISR and prevent the recurrence of ischemic attacks.
Acknowledgements This study was partly supported by grants from the National Natural Science Foundation of China (No. 81201078, 81100870, 81070923).
References 1 Sacco RL, Kargman DE, Gu Q et al. Race-ethnicity and determinants of intracranial atherosclerotic cerebral infarction. The Northern Manhattan Stroke Study. Stroke 1995; 26:14–20. 2 Wong LK. Global burden of intracranial atherosclerosis. Int J Stroke 2006; 1:158–9. 3 Chimowitz MI, Lynn MJ, Howlett-Smith H et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med 2005; 352:1305–16. 4 Kasner SE, Chimowitz MI, Lynn MJ et al. Predictors of ischaemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation 2006; 113:555–63.
© 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization
5 Famakin BM, Chimowitz MI, Lynn MJ et al. Causes and severity of ischemic stroke in patients with symptomatic intracranial arterial stenosis. Stroke 2009; 40:1999–2003. 6 Lutsep HL. Symptomatic intracranial stenosis: best medical treatment vs. intracranial stenting. Curr Opin Neurol 2009; 22:69–74. 7 Chimowitz MI, Lynn MJ, Derdeyn CP et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 2011; 365:993–1003. 8 Hussain MS, Fraser JF, Abruzzo T et al. Standard of practice: endovascular treatment of intracranial atherosclerosis. J Neurointerv Surg 2012; 4:397–406. 9 Liu X. Beyond the time window of intravenous thrombolysis: standing by or by stenting? Intervent Neurol 2012; 1:3–15. 10 Groschel K, Schnaudigel S, Pilgram SM, Wasser K, Kastrup A. A systematic review on outcome after stenting for intracranial atherosclerosis. Stroke 2009; 40:e340–7. 11 Zhu SG, Zhang RL, Liu WH et al. Predictive factors for in-stent restenosis after balloon-mounted stent placement for symptomatic intracranial atherosclerosis. Eur J Vasc Endovasc Surg 2010; 40:499– 506. 12 Yue X, Yin Q, Xi G et al. Comparison of BMSs with SES for Symptomatic Intracranial Disease of the Middle Cerebral Artery Stenosis. Cardiovasc Intervent Radiol 2011; 34:54–60. 13 Klein LW, Rosenblum J. Restenosis after successful percutaneous transluminal coronary angioplasty. Prog Cardiovasc Dis 1990; 32:365– 82. 14 Anstin GE, Ratliff NB, Hollman J, Tabei S, Phillips DF. Intimal proliferation of smooth muscle cells as an explanation for recurrent coronary artery stenosis after percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1985; 6:369–75. 15 Xia CF, Yin H, Borlongan CV. Kallikrein gene transfer protects against ischemic stroke by promoting glial cell migration and inhibiting apoptosis. Hypertension 2004; 43:452–9. 16 Tang Y, Shao Y, Su J et al. The Protein Therapy of Kallikrein in Cerebral Ischemic Reperfusion Injury. Curr Med Chem 2009; 16:4502–10. 17 Liu L, Zhang R, Liu K et al. Tissue kallikrein protects cortical neurons against in vitro ischemia-acidosis/reperfusion-induced injury through the ERK1/2 pathway. Exp Neurol 2009; 219:453–65. 18 Emanueli C, Salis MB, Chao J et al. Adenovirus-mediated human tissue kallikrein gene delivery inhibits neointima formation induced by interruption of blood flow in mice. Arterioscler Thromb Vasc Biol 2000; 20:1459–66. 19 Murakami H, Yayama K, Miao RQ, Wang C, Chao L, Chao J. Kallikrein gene delivery inhibits vascular smooth muscle cell growth and neointima formation in the rat artery after balloon angioplasty. Hypertension 1999; 34:164–70. 20 Porcu P, Emanueli C, Desortes E et al. Circulating tissue kallikrein levels correlate with severity of carotid atherosclerosis. Arterioscler Thromb Vasc Biol 2004; 24:1104–10. 21 Samuels OB, Joseph GJ, Lynn MJ et al. Standardized method for measuring intracranial arterial stenosis. AJNR Am J Neuroradiol 2000; 21:643–6.
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Correspondence: Xinfeng Liu* and Renliang Zhang*, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, China. E-mail: [email protected]; [email protected] 1 Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China 2 Davis Heart & Lung Research Institute, Ohio State University Medical Center, Columbus, OH, USA Received: 25 June 2013; Accepted: 10 October 2013; Published online 20 December 2013 †
These authors contributed equally to this work and share first authorship.
Conflicts of interest: None declared. DOI: 10.1111/ijs.12229 © 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization
Introduction Intracranial atherosclerotic stenosis of the major intracranial arteries is one of the most important risk factors of ischemic stroke, which accounts for 10–15% of all ischemic strokes (1). It is particularly prevalent in Chinese populations, with estimated incidence in stroke populations ranging from 33% to 50% (2). The Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) trial revealed, despite the best antithrombotic therapy, the rate of ischemic stroke in the territory of the high-grade (50–99%) stenotic artery was nearly 12% at 1 year (3), and the stroke rate was up to 18% at 1 year in the subgroup of patients with intracranial stenosis >70% (4). Even more important, strokes ipsilateral to the severe stenotic artery were hemispheric and often disabling (5). For these reasons, people paid more and more attention to percutaneous transluminal angioplasty with stenting (PTAS) for the symptomatic intracranial arterial stenosis intractable to medical therapy (6–9). A major concern for PTAS for the intracranial stenosis has been the incidence of in-stent restenosis (ISR) (10). In our previous studies, the rate of ISR after intracranial stenting with bare metal balloon-mounted stents was about 30% at a median follow-up of 7 months (11), and it seems more frequent with the Selfexpanding stents (8,12). The pathogenesis of ISR remains incompletely understood, maybe mainly due to the proliferation of intima associated with the inflammation after stenting (13,14). At present, there are no definite evidenced-based interventions to prevent ISR after intracranial stenting. A series of studies have confirmed the kallikrein-kinin system (KKS), including kallikrein, kininogen and kinin, plays an important role in the regulation of inflammation secondary to acute and chronic ischemic brain injury (15–17). Emanueli (18) found that hTK gene delivery can inhibit the formation of neointimal induced by the common carotid artery ligation in mice. Further study revealed hTK gene transfection in VSMC lead to increased secretion of TK and inhibition of VSMC proliferation (19). In addition, it was also observed that the serum TK levels were coincident with the carotid artery stenosis (20). The more severe the stenosis is, the higher the serum TK level is, and the serum TK decreased after carotid artery angioplasty and stent placement. These results suggest that KKS play an important regulatory role in vascular remodeling and TK may exert a beneficial infulence in the process of ISR. In this analysis, we hypothesized that the rate of ISR and the frequency of subsequent stroke or other vascular events would be reduced in TK-treated patients after PTAS. Vol 9, June 2014, 533–535
533
Protocols
W. Lan et al.
Table 1 The inclusion/exclusion criteria Inclusion criteria: 1. TIA or stroke in the MCA territory refractory to aggressive anti-platelet and regular statin therapy in 3 months 2. Symptomatic MCA M1 segment stenosis ≥70% confirmed with DSA 3. Successfully treated with PTAS without acute surgical complications in 12 h after operation 4. All patients provided fully informed consent Exclusion Criteria: 1. Using angiotensin-converting enzyme inhibitors (Because angiotensin-converting enzyme inhibitors can inhibit the degradation of kinin caused by kininase II (K II) ) 2. Severe cardiopulmonary dysfunction, chronic liver disease (A/G inversion, ALT increased 2-fold greater than normal), abnormal renal function (serum creatinine greater than 1·5 times normal) 3. Allergies, the history of allergy to multi-drug 4. The history of cerebral hemorrhage, brain tumors, brain trauma, cerebral embolism and other brain lesions 5. During pregnancy or breast-feeding 6. Not expected to complete follow-up
Methods Overview KPRASS is a Phase II, randomized, single-blinded, controlled trial. Patients with the symptomatic MCA M1 segment stenosis ≥70% and successfully treated with PTAS are the source group. The patients are prospectively followed for a minimum of one year and ISR will be evaluated with DSA at 6 and 12 months after PTAS. Patient population Patients with the symptomatic MCA severe stenosis and successfully treated with PTAS are the source group. No racial or gender groups are excluded. Participants are recruited from the inpatient stroke services of the Jinling Hospital, a university-affiliated Grade-A tertiary hospital in Nanjing. The sample consists of adults (age > 30) hospitalized of an ischemic stroke or TIA due to atherogenic cerebrovascular disease. Ischemic stroke is defined as rapidly developing clinical signs of focal disturbance of cerebral function lasting more than 24h. In the case of TIA or clinical stroke without lesions visualized on neuroimaging, a stroke neurologist confirms the diagnosis. Diagnostic evaluation is performed at the discretion of the treating physicians, but commonly including MRA, CT angiography (CTA), TCD and DSA. Patients with evidence of ≥70% MCA M1 segment confirmed with DSA are screened for final eligibility based upon the inclusion/exclusion criteria (Table 1). Randomization and blinding Eligible patients will be randomized by computer generated numbers in sealed opaque envelopes. A detailed neurological evaluation including the standardized assessments (such as NIHSS, Barthel Index etc.) is performed by the blinded study physician. Blinded raters obtain all follow up data. The patients are instructed not to reveal their treatment assignment. Vascular events, re-hospitalizations, and other clinical event are adjudicated by a physician blinded to treatment assignment. Experimental intervention Participants in TK-treatment group will receive intravenous infusions of kallikrein (0·15 PNAU/d, dissolved in 100 ml saline) for 7 days after PTAS and followed with oral administration of Pancre-
534
Vol 9, June 2014, 533–535
atic Kinionogenase Enteric-coated Tab (240U, 3/d) to the end of study. All the patients enrolled will receive aspirin (100 mg/d), clopidogrel (75 mg/d), and atorvastatin (20 mg/d) for the first 6 months and continue with the combination of aspirin and atorvastatin at the previous dosage. Study assessments The nature and frequency of cerebral ischemic events is recorded. Medications at the time of enrollment and specific data regarding vascular risk factors are gathered including age, gender, race, hypertension, diabetes mellitus, lipid disorder, coronary disease, smoking, alcohol consumption, and parental death from stroke. The National Institute of Health Stroke Scale (NIHSS) is administered, and functional status assessed using the Barthel Index (BI), and modified Rankin Scales (mRS). The MRI is applied to confirm the diagnosis and will be rechecked as needed during the follow-up period. Available laboratory data including platelet inhibitory rate by Thrombelastography (TEG) Platelet MappingTM, bradykinin (BK), tissue kallikrein (TK), cGMP, cAMP, high sensitivity C-reactive protein (hs-CRP), TNF-α, IL-6, LDL-Ch and HDL-Ch, casual or fasting plasma glucose is collected, in addition to results of cerebral imaging studies. A standardized DSA and PTAS are performed, and DSA is used to re-evaluate vascular lesion and the ISR at 6 months and 12 months. Selected baseline measurements and study assessments can be found in Table 2. Ethics approval The study has received an approval of the Jinling hospital ethical committee. And this trial is registered in clinicaltrials.gov (NCT01558245). Data management Data quality control includes data checks that are built into this data system to ensure the integrity of all data entered for each study participant. All study imaging data is centrally reviewed to confirm adequate imaging quality and completeness. Initial determination of MCA stenosis for eligibility is made using the WASID technique (21). Relevant angiographic images are reviewed by a blinded neuroradiologist for final determination of degree of stenosis. © 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization
Protocols
W. Lan et al.
Table 2 Study assessments Baseline 1 month 6 months 12 months History and physical NIH Stroke Scale Functional assessments: Barthel Index, Modified Rankin Scale Thrombelastography (TEG) Platelet MappingTM MRI DSA Laboratory data
X X X
X X
X X X X
X
X X
X X
X
X
X X
X X
Sample size To achieve a sample size using Power and sample size program, a 0·05 significance level and 80% power was first calculated. Pilot data was obtained from 10 patients in which the in-stent restenosis rate was 10% in the intervention group, and around 30% in the control group. The sample size required is 90. So, a 10% drop out rate was assumed, and the target for enrollment is 99 participants.
Conclusion The prevention for ISR is of great importance to ischemic stroke patients for reducing recrudescence, disability and improving worse outcomes. KPRASS will determine whether the combination with kallikrein can reduce the incidence of ISR and prevent the recurrence of ischemic attacks.
Acknowledgements This study was partly supported by grants from the National Natural Science Foundation of China (No. 81201078, 81100870, 81070923).
References 1 Sacco RL, Kargman DE, Gu Q et al. Race-ethnicity and determinants of intracranial atherosclerotic cerebral infarction. The Northern Manhattan Stroke Study. Stroke 1995; 26:14–20. 2 Wong LK. Global burden of intracranial atherosclerosis. Int J Stroke 2006; 1:158–9. 3 Chimowitz MI, Lynn MJ, Howlett-Smith H et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med 2005; 352:1305–16. 4 Kasner SE, Chimowitz MI, Lynn MJ et al. Predictors of ischaemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation 2006; 113:555–63.
© 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization
5 Famakin BM, Chimowitz MI, Lynn MJ et al. Causes and severity of ischemic stroke in patients with symptomatic intracranial arterial stenosis. Stroke 2009; 40:1999–2003. 6 Lutsep HL. Symptomatic intracranial stenosis: best medical treatment vs. intracranial stenting. Curr Opin Neurol 2009; 22:69–74. 7 Chimowitz MI, Lynn MJ, Derdeyn CP et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 2011; 365:993–1003. 8 Hussain MS, Fraser JF, Abruzzo T et al. Standard of practice: endovascular treatment of intracranial atherosclerosis. J Neurointerv Surg 2012; 4:397–406. 9 Liu X. Beyond the time window of intravenous thrombolysis: standing by or by stenting? Intervent Neurol 2012; 1:3–15. 10 Groschel K, Schnaudigel S, Pilgram SM, Wasser K, Kastrup A. A systematic review on outcome after stenting for intracranial atherosclerosis. Stroke 2009; 40:e340–7. 11 Zhu SG, Zhang RL, Liu WH et al. Predictive factors for in-stent restenosis after balloon-mounted stent placement for symptomatic intracranial atherosclerosis. Eur J Vasc Endovasc Surg 2010; 40:499– 506. 12 Yue X, Yin Q, Xi G et al. Comparison of BMSs with SES for Symptomatic Intracranial Disease of the Middle Cerebral Artery Stenosis. Cardiovasc Intervent Radiol 2011; 34:54–60. 13 Klein LW, Rosenblum J. Restenosis after successful percutaneous transluminal coronary angioplasty. Prog Cardiovasc Dis 1990; 32:365– 82. 14 Anstin GE, Ratliff NB, Hollman J, Tabei S, Phillips DF. Intimal proliferation of smooth muscle cells as an explanation for recurrent coronary artery stenosis after percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1985; 6:369–75. 15 Xia CF, Yin H, Borlongan CV. Kallikrein gene transfer protects against ischemic stroke by promoting glial cell migration and inhibiting apoptosis. Hypertension 2004; 43:452–9. 16 Tang Y, Shao Y, Su J et al. The Protein Therapy of Kallikrein in Cerebral Ischemic Reperfusion Injury. Curr Med Chem 2009; 16:4502–10. 17 Liu L, Zhang R, Liu K et al. Tissue kallikrein protects cortical neurons against in vitro ischemia-acidosis/reperfusion-induced injury through the ERK1/2 pathway. Exp Neurol 2009; 219:453–65. 18 Emanueli C, Salis MB, Chao J et al. Adenovirus-mediated human tissue kallikrein gene delivery inhibits neointima formation induced by interruption of blood flow in mice. Arterioscler Thromb Vasc Biol 2000; 20:1459–66. 19 Murakami H, Yayama K, Miao RQ, Wang C, Chao L, Chao J. Kallikrein gene delivery inhibits vascular smooth muscle cell growth and neointima formation in the rat artery after balloon angioplasty. Hypertension 1999; 34:164–70. 20 Porcu P, Emanueli C, Desortes E et al. Circulating tissue kallikrein levels correlate with severity of carotid atherosclerosis. Arterioscler Thromb Vasc Biol 2004; 24:1104–10. 21 Samuels OB, Joseph GJ, Lynn MJ et al. Standardized method for measuring intracranial arterial stenosis. AJNR Am J Neuroradiol 2000; 21:643–6.
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