Debra A. Lewis

A New Endoluminal, Flow-Disrupting Device for Treatment of Saccular Aneurysms

Background and Purpose— We report a preclinical study of a new endoluminal device for aneurysm occlusion to test the hypothesis that the device, even without use of intrasaccular coil placement, could occlude saccular aneurysms without causing substantial parent artery compromise or compromise of adjacent, small branch arteries. Methods— The Pipeline Neuroendovascular Device (Pipeline NED; Chestnut Medical Technologies, Inc) is a braided, tubular, bimetallic endoluminal implant aimed at occlusion of saccular aneurysms through flow disruption along the aneurysm neck. The device was implanted across the necks of 17 elastase-induced aneurysms in the New Zealand white rabbit model and followed for 1 month (n=6), 3 months (n=5), and 6 months (n=6). In each subject, a second device was implanted in the abdominal aorta to cover the origins of lumbar arteries. Aneurysm occlusion rates by angiography (grade 1, complete occlusion; grade 2, near-complete occlusion; and grade 3, incomplete occlusion) were documented. Percent area stenosis of the parent arteries was calculated. Presence of distal emboli in the downstream vessels in the parent artery and branch artery stenosis or occlusion was noted. Results— Grades 1, 2, and 3 occlusion rates were noted in 9 (53%), 6 (35%), and 2 (12%) of 17 aneurysms, respectively, indicating an 88% rate of complete or near complete occlusion. No cases of branch artery occlusion or distal emboli in the downstream vessels of the parent artery, specifically the subclavian artery, were seen. Parent artery compromise from neointimal hyperplasia was minimal in most cases. Conclusions— The Pipeline NED is a trackable, bio- and hemocompatible device able to occlude saccular aneurysms with preservation of the parent artery and small, adjacent branch vessels.

A Second-Generation, Endoluminal, Flow-Disrupting Device for Treatment of Saccular Aneurysms

BACKGROUND AND PURPOSE: We report a preclinical study of a second-generation endoluminal device (Pipeline Embolization Device [PED-2] for aneurysmal occlusion and compare the PED-2 with its first-generation predecessor (PED-1). MATERIALS AND METHODS: Our Institutional Animal Care and Use Committee approved all studies. The PED-2 is a braided endoluminal, flow-diverting device and was implanted across the necks of 18 elastase-induced aneurysms in New Zealand white rabbits and followed for 1 month (n = 6), 3 months (n = 6), and 6 months (n = 6). A second PED-2 was implanted in the abdominal aorta to cover the origins of the lumbar arteries. Angiographic occlusion rates were documented as complete, near-complete, and incomplete. Parent artery percent diameter stenosis was calculated. Results were compared with a previous publication focused on the PED-1, with use of the same model. We compared ordinal outcomes using Fisher Exact or χ2 tests. We compared continuous data using analysis of variance. RESULTS: Occlusion rates (complete and incomplete) for the PED-2 were noted in 17 cases (94%) and 1 (6%), respectively, compared with 9 cases of complete (53%) and 8 (47%) of incomplete occlusion with the PED-1 (P = .0072). No incidents of branch artery occlusion or distal emboli in vessels downstream of the parent artery were observed with the PED-2. Parent artery neointimal hyperplasia was minimal in most cases and was significantly less than in the PED-1. CONCLUSIONS: The PED-2 is a biocompatible and hemocompatible device that occludes saccular aneurysms while preserving the parent artery and small-branch vessels in our animal model.

Insulin-like growth factor binding protein-4 protease produced by smooth muscle cells increases in the coronary artery after angioplasty

Abstract —Insulin-like growth factor (IGF)-I stimulates vascular smooth muscle cell (VSMC) migration and proliferation, which are fundamental to neointimal hyperplasia in postangioplasty restenosis. IGF-I action is modulated by several high-affinity IGF binding proteins (IGFBPs). IGFBP-4 is the predominant IGFBP produced by VSMCs and is a potent inhibitor of IGF-I action. However, specific IGFBP-4 proteases can cleave IGFBP-4 and liberate active IGF-I. In this study, we document IGFBP-4 protease produced by human and porcine coronary artery VSMCs in culture as pregnancy-associated plasma protein-A (PAPP-A). This was shown by a distinctive IGFBP-4 cleavage pattern, specific inhibition of IGFBP-4 protease activity with PAPP-A polyclonal antibodies, and immunorecognition of PAPP-A by monoclonal antibodies. Furthermore, we found a 2-fold increase in IGFBP-4 protease activity in injured porcine VSMC cultures in vitro (P <0.05). We also evaluated IGFBP-4 protease/PAPP-A expression in vivo after coronary artery balloon injury. Twenty-five immature female pigs underwent coronary overstretch balloon injury, and vessels were examined at defined time points after the procedure. Abundant PAPP-A expression was observed in the cytoplasm of medial and neointimal cells 7, 14, and 28 days after angioplasty (P <0.01 vs control). The highest PAPP-A labeling indices were located in the neointima (36.1±2.1%) and the media (31.7±1.2%) 28 days after injury. Western blot analysis confirmed increased PAPP-A in injured vessels. PAPP-A, a regulator of IGF-I bioavailability through proteolysis of IGFBP-4, is thus expressed by VSMCs in vitro and in restenotic lesions in vivo. These results suggest a possible role for PAPP-A in neointimal hyperplasia.

Balloon-Assisted Coiling of Intracranial Aneurysms: Evaluation of Local Thrombus Formation and Symptomatic Thromboembolic Complications

BACKGROUND AND PURPOSE: Remodeling balloons are used to assist in endovascular coiling of aneurysms. We evaluated our experience with balloon-assisted coiling (BAC) in an attempt to determine whether this technique increased the rate of thrombus formation or symptomatic thromboembolic complications. MATERIALS AND METHODS: In 3 years, we treated 221 patients with intracranial aneurysms. Statistical analysis was performed to assess whether BAC increased the rate of thrombus formation or symptomatic thromboembolic complications. Patient demographics, aneurysm size, location, neck width, antiplatelet therapy, and rupture status were evaluated. RESULTS: We detected no statistically significant difference in rates of thrombus formation (14% versus 9% with and without BAC, respectively, P = 0.35) or symptomatic thromboembolic events (7% versus 5% with and without BAC, respectively, P = 0.76), though our power to detect small differences was limited. There was also no correlation with age, sex, rupture status, aneurysm size, or location. There was a significant increase in the rates of thrombus formation (6% versus 16%, P = 0.02) and symptomatic thromboembolic complications (3% versus 10%, P = 0.04) in aneurysms that were classified as narrow- or wide-necked, respectively. The use of clopidogrel was associated with a decrease in the rate of complications (P = 0.01). CONCLUSION: In this series, we detected no significant increase in the rates of either intraprocedural thrombus formation or symptomatic thromboembolic events in patients treated with BAC. Larger studies are required to confirm our observations. Wide-necked aneurysms were independently associated with increased rates of thrombus formation and symptomatic thromboembolic complications, whereas the use of clopidogrel was protective (P = 0.01).

The Woven EndoBridge: A New Aneurysm Occlusion Device

BACKGROUND AND PURPOSE: The WEB device is an intrasaccular ellipsoid braided-wire embolization device designed to provide flow disruption along the aneurysm neck. The purpose of this study was to evaluate, in an in vivo aneurysm model, the acute and chronic performance of the WEB device regarding immediacy, degree, and durability of aneurysm occlusion. MATERIALS AND METHODS: The WEB device was implanted in 24 elastase-induced aneurysms in New Zealand white rabbits and followed for 1, 3, 6, and 12 months (n = 6 at all time points). Degree of intra-aneurysmal flow disruption was graded on a 4-point scale based on DSA within 10 minutes following device implantation. Chronic aneurysm occlusion was rated by using a 3-point scale. All aneurysms were harvested for histologic analysis. RESULTS: Immediate postimplant grade 1 (complete flow cessation) was noted in 7 (29%) of 24 cases. Grade 2 (near-complete flow cessation) was noted in 13 (54%) of 24 cases. At follow-up, complete occlusion was noted in 8 (33%) of 24 cases. Near-complete aneurysm occlusion was noted in 14 (58%) of 24 cases, while incomplete occlusion was noted in 2 (8%) cases. Stable aneurysm occlusion was present in 7 (29%) of 24 cases; progressive occlusion, in 14 (58%); and recanalization, in 3 (13%) cases. Histologic findings included aneurysm cavities filled with organized thrombus with connective tissue across the aneurysm neck. CONCLUSIONS: The WEB device in experimental aneurysms demonstrated promising rates of immediate and long-term aneurysm occlusion.

Gender and transcriptional regulation of NO synthase and ET-1 in porcine aortic endothelial cells

Experiments were designed to determine whether normal fluctuations in sex steroid hormones alter gene transcription for endothelial nitric oxide synthase (NOS) and preproendothelin-1 (prepro-ET-1). Aortic endothelial cells were removed from adult, gonadally intact male and female or ovariectomized Yorkshire pigs. Endothelial cells were prepared for Northern blot analysis, Western blot analysis or enzyme activity. Nitric oxide products (NOx) and endothelin-1 (ET-1) in plasma were measured by chemiluminescence and radioimmunoassay, respectively. Northern blot analysis identified single bands corresponding to endothelial NOS and prepro-ET-1. Quantification of the blots showed an increase in expression of mRNA for both endothelial NOS and prepro-ET-1 in ovariectomized pigs compared with gonadally intact male and female pigs. There were no differences in amount of endothelial NOS protein identified by Western blot analysis among groups. On the contrary, plasma concentrations of NOx were significantly decreased in ovariectomized pigs, and there were no differences either in the concentrations of ET-1 in the plasma or extracts from the coronary arteries. These results suggest that expression of endothelial NOS and prepro-ET-1 may be regulated at transcriptional level by ovarian hormones. In addition, the ovarian hormones may regulate production of these endothelium-derived factors at the posttranscriptional level.Experiments were designed to determine whether normal fluctuations in sex steroid hormones alter gene transcription for endothelial nitric oxide synthase (NOS) and preproendothelin-1 (prepro-ET-1). Aortic endothelial cells were removed from adult, gonadally intact male and female or ovariectomized Yorkshire pigs. Endothelial cells were prepared for Northern blot analysis, Western blot analysis or enzyme activity. Nitric oxide products (NOx) and endothelin-1 (ET-1) in plasma were measured by chemiluminescence and radioimmunoassay, respectively. Northern blot analysis identified single bands corresponding to endothelial NOS and prepro-ET-1. Quantification of the blots showed an increase in expression of mRNA for both endothelial NOS and prepro-ET-1 in ovariectomized pigs compared with gonadally intact male and female pigs. There were no differences in amount of endothelial NOS protein identified by Western blot analysis among groups. On the contrary, plasma concentrations of NOx were significantly decreased in ovariectomized pigs, and there were no differences either in the concentrations of ET-1 in the plasma or extracts from the coronary arteries. These results suggest that expression of endothelial NOS and prepro-ET-1 may be regulated at transcriptional level by ovarian hormones. In addition, the ovarian hormones may regulate production of these endothelium-derived factors at the posttranscriptional level.

Cellular Mechanisms of Aneurysm Occlusion after Treatment with a Flow Diverter

PURPOSE To characterize the progression of healing across aneurysm necks following treatment with a flow diverter in a rabbit aneurysm model. MATERIALS AND METHODS With institutional animal care and use committee approval, saccular aneurysms were created in 20 rabbits and treated with flow diverters. On days 1, 3, and 7 and weeks 4 and 8 after implantation, the aneurysm and the device-implanted vessel were harvested. En face staining of the gross specimen was performed for endothelial cells, endothelial progenitor cells, smooth muscle cells, and inflammatory cells. RESULTS The parent artery segments covered by the flow diverters were completely devoid of endothelial cells at 1 and 3 days but had completely reendothelialized by 7 days. At all time points, the struts along the patent portions of the aneurysm necks harbored scattered tissue islands composed exclusively of inflammatory cells. At 4 and 8 weeks, all samples contiguous with the tissue along the parent arteries had translucent tissue present along the occluded segments of the aneurysm neck. The vast majority of endothelial cells were contiguous with the parent artery and had smooth muscle cells underlying them. Endothelial progenitor cells were not observed along the neck of any aneurysm. Aneurysm closure was noted only when complete or nearly complete endothelialization over the device struts was present. CONCLUSION The initial event following flow diversion treatment is adherence of clusters of inflammatory cells across the aneurysm neck. Endothelialization is relatively delayed and derived exclusively from cells in the adjacent parent artery.

Preliminary Results of the Luna Aneurysm Embolization System in a Rabbit Model: A New Intrasaccular Aneurysm Occlusion Device

BACKGROUND AND PURPOSE: Recent advances in endovascular devices have been aimed at providing high density, mesh-like metallic materials across the aneurysm neck, in place of coil technology. Therefore our aim was to report the in vivo preclinical performance of a self-expanding intrasaccular embolization device. MATERIALS AND METHODS: Elastase-induced aneurysms were created in 12 rabbits. Each aneurysm was embolized with a Luna AES. DSA was performed preimplantation; 5, 10, and 30 minutes postimplantation; and at 1 month in 12 rabbits and at 3 months in 8 rabbits. Early postimplantation intra-aneurysmal flow was graded as unchanged, moderately diminished, or completely absent. One- and 3-month DSAs were graded by using a 3-point scale (complete, near-complete, or incomplete occlusion). Aneurysms were harvested for gross and microscopic histologic evaluation at 1 month (n = 4) and at 3 months (n = 8). Tissues within the aneurysm dome and across the aneurysm neck were assessed by using HE staining. RESULTS: Ten (83%) of 12 aneurysms demonstrated complete cessation of flow within 30 minutes of device implantation. At 1-month follow-up, 10 (83%) of 12 aneurysms were completely occluded. At 3 months, 7 of 8 (88%) aneurysms remained completely occluded. One-month gross examination in 4 rabbits demonstrated that membranous tissue completely covered the device in 3 subjects (75%). Microscopic examination showed that 3 aneurysms had loose connective tissue filling the aneurysm cavity. Three-month gross and microscopic examinations demonstrated membranous tissue completely covering the device, loose connective tissue filling the aneurysm cavity, and neointima formation crossing the aneurysm neck in 8 of 8 (100.0%) subjects. CONCLUSIONS: The Luna AES achieved high rates of complete angiographic occlusion and showed promising histologic findings in the rabbit aneurysm model.

Plasma Nitric Oxide Before and After Smoking Cessation with Nicotine Nasal Spray

Nicotine may affect cardiovascular function through release of neurotransmitters from autonomic nerves or release of vasoactive substances from the vascular endothelium. Nitric oxide is a neurotransmitter and endothelium‐derived factor that reduces tone of vascular smooth muscle. Experiments were designed to determine whether or not use of nicotine nasal spray for smoking cessation affects plasma levels of nitric oxide. Forty smokers self‐administered nicotine by nasal spray (one 0.5 mg spray to each nostril). Blood samples were taken before the use of the nasal spray and at treatment day 7 for the measurement of cotinine by high pressure liquid chromatography and nitric oxide (NOx) by chemiluminescence. Age‐comparable controls were never‐smokers nonnicotine users recruited from laboratory personnel. Mean plasma concentrations of NOx from smokers before treatment were significantly greater compared with nonsmokers (23 ± 10, n = 40 and 15 ± 6, n = 13 nmoles/mL [mean ± SD], respectively, P < 0.01). Plasma NOx in smokers was not significantly correlated with the average daily number of cigarettes smoked (r2 = 0.02, P > 0.05) but was positively and linearly correlated with plasma cotinine (r2 = 0.13, P < 0.02). In 32 self‐reported abstinent smokers (confirmed by expired carbon monoxide < 9 ppm) using nicotine nasal spray, cotinine decreased by 64% from pretreatment levels of 284 ± 103 to posttreatment levels of 90 ± 58 ng/mL. Plasma NOx was unchanged and went from 23.0 ± 10.1 at pretreatment to 21 ± 12 nmoles/mL with nicotine treatment. These results suggest that nicotine‐use, independent of cigarette smoking, affects plasma NOx.

Patency of Branches after Coverage with Multiple Telescoping Flow-Diverter Devices: An In Vivo Study in Rabbits

BACKGROUND AND PURPOSE: The safety of placing multiple overlapped endoluminal flow diverters remains unclear because small eloquent branch arteries theoretically could become occluded by these devices. We placed single and multiple flow diverters over small branch arteries in rabbit aortas to determine the incidence of branch artery occlusion. MATERIALS AND METHODS: Flow diverters (PED) were placed into 22 female New Zealand white rabbits abdominal aortas to cover ≥1 lumbar artery. Animals were divided into 3 groups (single PED, n = 9; double PED with 2 telescoped/overlapped devices, n = 7; and triple PED, with 3 telescoped/overlapped devices, n = 6) and were followed for 6 or 12 months. DSA was performed at follow-up. Subsequently, the tissue was processed, sectioned, and stained with H&E for histologic evaluation, histomorphometry, and analysis. RESULTS: All the lumbar arteries covered by devices were clearly patent on angiography. Partial neointima covered the ostia of the branch vessels, but demonstrable patent lumens at the ostia in all cases were present. Neointima hyperplasia was minimal in the single-PED-group animals. The measured neointima was thicker for the double- and triple-PED groups compared with the single-PED group (P < .05). However, in all groups, the mean thickness of the neointima was ≤0.2 mm, and the percentage stenosis of the parent artery was <15% and 18% for 6 and 12 months, respectively. There was no significant inflammatory response in any group. CONCLUSIONS: Small branch arteries remain patent even when covered by multiple overlapped PED flow-diverter devices.