Neointimal Thickness Research Articles

Vascular Healing After Biodegradable Polymer Sirolimus-Eluting Versus Durable Polymer Everolimus-Eluting Stents in Chronic Total Occlusions.

Biodegradable polymer stents may reduce the risk of neoatherosclerosis and stent thrombosis. Limited data is available for biodegradable polymer sirolimus-eluting stent (BP-SES) and durable polymer drug-eluting stents (DP-EES) in chronic total occlusions (CTO). This study was to evaluate healing patterns of BP-SES versus DP-EES in CTO at 3 and 13 months based on optical coherence tomography (OCT). The TARGET-CTO study is a prospective, multicenter, randomized noninferiority controlled trial for BP-SES compared to DP-EES in CTO. In the current predefined subanalysis, 44 consecutive patients underwent OCT follow-up at 3 and 13 months. The primary endpoint was mean neo-intimal thickness at 3 months. At 3 months, mean neo-intimal thickness was 47.6 ± 15.7 µm in BP-SES and 62.5 ± 37.3 µm in DP-EES (p = 0.384), meeting the noninferiority for BP-SES (pnoninferiority < 0.001). Mean neo-intimal thickness at 13 months was 76.4 ± 34.1 µm in BP-SES and 106.6 ± 54.9 µm in DP-EES (p = 0.086). No significant differences in strut coverage were observed at 3 or 13 months. At 13 months significantly higher percentages of frames with layered neo-intima and neoatherosclerosis were observed in DP-EES compared to BP-SES (p = 0.015 and p = 0.021, respectively). BP-SES was noninferior to DP-EES in terms of neo-intimal thickness at 3 months and healing responses at 3-month follow-up were comparable. At 13 months, less advanced neoatherosclerosis patterns were observed in BP-SES as compared to DP-EES.

Effect of rapamycin-eluting stents on in-stent restenosis and early inflammatory response in coronary artery narrowing animal models

Objectiveit was to evaluate the efficacy and safety of rapamycin-eluting stents at different doses in the treatment of coronary artery narrowing in miniature pigs.Methodsa total of 20 miniature pigs were randomly assigned into four groups: S1 group (low-dose rapamycin-coated stent, 55 µg/mm2), S2 group (medium-dose rapamycin-coated stent, 120 µg/mm2), S3 group (high-dose rapamycin-coated stent, 415 µg/mm2), and D0 group (bare metal stent). The stent size was 3.0 mm × 18 mm, with an over-expansion ratio of 1.1. Each group consisted of five pigs. Stent implantation was followed by euthanasia and tissue collection after 1 month. Vascular measurements, inflammatory response scores, cardiovascular injury scores, endothelialization scores, liver and kidney function indices, and myocardial injury markers were compared among the groups.Resultsthe neointimal thickness in the S2 and S3 groups was significantly lower than that in the S1 and D0 groups (S1 group: 24.08 ± 3.95, S2 group: 1.86 ± 0.28, S3 group: 2.72 ± 0.74, D0 group: 22.85 ± 3.15, P < 0.05). The residual lumen area in the S2 and S3 groups was significantly larger than that in the S1 and D0 groups (S1 group: 2.73 ± 0.51, S2 group: 4.25 ± 0.78, S3 group: 3.91 ± 0.73, D0 group: 2.91 ± 0.44, P < 0.05). The neointimal area in the S2 and S3 groups was significantly smaller than that in the S1 and D0 groups (S1 group: 3.44 ± 0.84, S2 group: 1.78 ± 0.25, S3 group: 2.07 ± 0.41, D0 group: 3.43 ± 0.72, P < 0.05). The degree of lumen narrowing in the S2 and S3 groups was significantly lower than that in the S1 and D0 groups (S1 group: 44.25 ± 3.66%, S2 group: 14.19 ± 2.01%, S3 group: 15.29 ± 2.45%, D0 group: 21.79 ± 3.51%, P < 0.05). The inflammation scores of coronary artery walls in the S2 and S3 groups of miniature pigs were markedly lower than those in the S1 and D0 groups (P < 0.05). The cardiovascular injury scores (P = 0.072) and endothelialization scores (P = 0.085) differed slightly among the four groups (P > 0.05). Post-operative liver function indicators (alanine transaminase, aspartate transaminase), kidney function indicators (blood urea nitrogen, serum creatinine), and myocardial injury markers (creatine kinase, creatine kinase-MB) also showed neglectable differences among the four groups (P > 0.05).Conclusionmedium and high doses of rapamycin-eluting stents effectively inhibit neointimal hyperplasia and local vascular inflammatory response in miniature pigs without causing damage to liver and kidney functions or myocardial cells. These stents demonstrate high efficacy and safety. Rapamycin-coated coronary stents, as an effective treatment for coronary artery stenosis, may achieve further improvement in therapeutic efficacy through optimization of drug dosage and stent design.

Comparison of Vessel Responses Following Combined Sirolimus-Eluting and Endothelial Progenitor Cell Stent and Ultra-Thin Sirolimus-Eluting Stent Implantation by Serial Optical Coherence Tomography and Coronary Angioscopy: A Multicenter Observational Study.

A dual-therapy sirolimus-eluting and CD34+ antibody-coated Combo Stent (DTS) has been developed to enhance endothelization and capture endothelial progenitor cells; however, vessel responses following DTS implantation remain unclear. Therefore, we evaluated early- and mid-term intravascular characteristics of DTS using intravascular imaging modalities. This multicenter, prospective, observational study enrolled 88 patients (95 lesions) who underwent DTS (43 patients, 48 lesions) or sirolimus-eluting Orsiro stent (SES, 45 patients, 47 lesions) implantation. Serial optical coherence tomography (OCT) and coronary angioscopy (CAS) findings were compared between the groups at 1 and 12 months.The OCT findings were similar between the DTS and SES groups at 1 month, including the covered strut rate (84.21±9.50% versus 80.56±17.68%, P=0.27). CAS findings were also comparable despite a more severe yellow coloration observed in the DTS group (P=0.006). At 12 months, OCT findings revealed that the covered and adequate strut coverage (≥40 μm) rates were significantly higher (99.27±0.95% versus 95.46±5.56%, P<0.001 and 88.90±10.15% versus 72.96±16.48%, P<0.001) and neointimal thickness was significantly thicker (152.16±70.31 versus 84.39±29.80 μm, P<0.001) in DTS than in SES. The malapposed strut rate was significantly higher in SES than in DTS (0.04±0.18% versus 0.82±1.87%, P=0.018). CAS revealed that the yellow coloration (P=0.049) and subclinical intrastent thrombus (P=0.019) were less severe in DTS than in SES at 12 months. In conclusion, DTS provided better advantages regarding strut coverage and plaque stabilization compared to SES. However, given the observational nature of this study, further randomized controlled trials are needed to confirm these findings.

Magnesium-based bioresorbable flow diverter for intracranial aneurysms: a pilot study of biocompatibility and bioresorption in a rabbit vascular model

BackgroundBioresorbable flow diverters (BRFDs) have the potential to solve several problems associated with conventional permanent flow diverters. We have constructed bare and poly-L-lactic acid (PLLA)-coated magnesium BRFDs (MgBRFDs) using a...

MicroRNA-18a-5p promotes vascular smooth muscle cell phenotypic switch by targeting Notch2 as therapeutic targets in vein grafts restenosis

Vascular smooth muscle cells (VSMCs) phenotype switching plays a crucial role in vein graft restenosis following coronary artery bypass grafting (CABG) surgery. To discover novel clinically relevant therapeutic targets for vein graft restenosis after CABG, we therefore investigated whether miRNA-18a-5p mediated phenotype switching plays a critical role in the development of vein graft restenosis. We studied miRNA-18a-5p expression in plasma samples of patients with or without vein graft restenosis at 1, 3 and 5 years after coronary artery bypass graft surgery, and in normal vs. atherosclerotic human femoral artery samples, to prove its role in VSMC phenotype switching. We found that the expression of miRNA-18a-5p significantly increased in vein grafts restenosis rat model after bypass surgery at 7, 14, 28 days and human blood specimens with vein grafts failure after grafting surgery. Through gain- and loss-of-function approaches, we determined that miRNA-18a-5p affects VSMC proliferation, migration, differentiation, and contractility. Notch2 was found to be a direct target of miRNA-18a-5p, which is critical for VSMC phenotype switching. Finally, miRNA-18a-5p knockdown used miRNA sponge via AAV6 locally delivery in vivo, miRNA-18a-5p sponge gene transfer therapy reduced the neointimal area, neointimal thickness, and intimal/media area ratio in vein grafts compared with the controls and improved vein graft hemodynamics. miRNA-18a-5p is a critical modulator of VSMC phenotypic switch during development of vein graft restenosis by downregulating Notch2, therefore targeting miRNA-18a-5p may be a helpful strategy for the treatment of vein grafts restenosis or failure after CABG surgery.

Clinical Application of DynaCT in the Study of Vascular Neointimal Hyperplasia Characteristics after Option Filter Placement.

The objective of this study was to analyze neointimal hyperplasia of the inferior vena cava (IVC) after Option filter implantation by DynaCT and to provide a reference for the safety of effective neointimal hyperplasia cutting after long retrieval window filter implantation in vivo. Clinical data on 22 patients with Option filters were retrospectively analyzed. DynaCT was used to analyze the characteristics of neointimal hyperplasia after filter implantation, including the distribution of neointimal hyperplasia and the maximum thickness of the neointimal hyperplasia. Correlation analysis was performed between the measurement results and the number of times the inner membrane of the filter was cut during filter retrieval, and correlation analysis also was performed between the measurement results and the time of filter placement. As measured by DynaCT, the neointimal hyperplasia after filter placement was located around the barbs of the filter plug, and the maximum neointimal hyperplasia thickness was located in the 1 to 5 points of the IVC. There was a linear trend between neointimal hyperplasia thickness of the IVC and filter neointimal cutting times by the retrieval catheter after filter placement. Correlation analysis showed a correlation coefficient of r = 0.609 (P = 0.003), indicating a significant correlation between the two. There also was a linear trend between neointimal hyperplasia thickness and implantation time. Correlation analysis showed that the correlation coefficient was r = 0.36 (P = 0.102), and the correlation between the two was not significant. Based on DynaCT, the characteristics of IVC neointimal hyperplasia after Option filter implantation were analyzed, and the cutting force and direction of neointimal hyperplasia could be controlled effectively and safely by changing the filter retrieval catheter. we can effectively and safely cut the hyperplastic intima by modifying the filter retrieval catheter to control the cutting force and direction and provide a reference for the safe and effective retrieval of the long-retrieval-time window filter after implantation in the body.

Long-Term Clinical Outcomes of Polymer-Free Sirolimus-Eluting Stent and Polymer-Coated Sirolimus-Eluting Stent in Patients with Type 2 Diabetes.

Polymer-free sirolimus-eluting stent (PF-SES) possess multiple properties improving targeted drug elution and in-stent reendothelialization without the presence of polymers. The long-term clinical performance comparison between PF-SES and the latest generation polymer-coated sirolimus-eluting stents (SES), particularly regarding intravascular imaging assessment and in the type 2 diabetes mellitus (DM) population, remains unexplored. We conducted a retrospective study involving 2646 diabetes patients meeting coronary artery disease (CAD) criteria underwent coronary stents in the real-world. All patients were divided into the PF-SES group and the SES group. Optical coherence tomography (OCT) was used to evaluate the imaging characteristics of in-stent reendothelialization. Patient information between the two groups was systematically compared in hospital and at 5-year follow-up. In terms of basic characteristics, the proportion of current smoker and stable angina patients in the PF-SES group was significantly higher than that in the SES group. The PF-SES group exhibited significantly higher rate of left anterior descending (LAD) lesion and more stents per patients compared to the SES group. The value of minimum lumen area (MLA), neointimal area (NA) and neointimal thickness (NT) were higher in the PF-SES group. Additionally, the occurrence rates of heterogeneous, lipid layer, intimal tears, thrombi, and micro-vessels were notably lower in the PF-SES group compared to the SES group. A higher all-cause mortality was observed in the SES cohort. PF-SES could effectively improve in-stent reendothelialization in patients with type 2 DM, with positive effects on survival rate and may, therefore, be considered as an alternative treatment option for improving clinical long-term outcomes.

Randomized Comparison of NovelLow-Dose Sirolimus-Eluting Biodegradable Polymer Stent vsSecond-Generation DES: TARGET-IV NA Trial.

Drug-eluting stents (DESs) with controlled antiproliferative drug release reduce restenosis risk, but durable polymers can delay healing and inhibit reendothelialization. The Firehawk biodegradable polymer sirolimus-eluting stent (BP-SES) has a fully biodegradable sirolimus-containing polymer coating localized to recessed abluminal grooves on the stent surface and delivers roughly one-third the drug dose of other DESs. We report the primary results of the TARGET-IV NA (Firehawk Rapamycin Target Eluting Coronary Stent North American Trial) randomized controlled trial comparing clinical outcomes with BP-SES vs currently used second-generation DESs. The TARGET-IV NA study was a prospective, multicenter, single-blind, 1:1 randomized noninferiority trial comparing the BP-SES with control in North America and Europe among patients undergoing percutaneous coronary intervention for chronic or acute coronary syndromes. The primary endpoint was target lesion failure (TLF) at 12months (composite of cardiac death, target vessel-related myocardial infarction, or ischemia-driven target lesion revascularization). The primary analysis (intention-to-treat) tested noninferiority of BP-SES vs control using an absolute margin of 3.85% and 1-sided α of 0.025. Noninferiority-powered secondary endpoints were tested in an optical coherence tomography substudy (endpoint: mean neointimal hyperplasia thickness) and an angiography substudy (endpoint: in-stent late lumen loss). A total of 1,720 patients (mean age 66 years; 74% male) with 2,159 lesions were randomly allocated to receive either BP-SES (860 patients, 1,057 lesions) or control second-generation DES (860 patients, 1,084 lesions). Atotal of 61% of patients presented with stable coronary disease, 32% had unstable angina, and 7% had non-ST-segment elevation myocardial infarction (NSTEMI) or recent ST-segment elevation myocardial infarction. The rate of TLF with BP-SES was noninferior to control at 12months (3.4% vs 3.3%, absolute risk difference 0.13%, upper bound 97.5%CI: 2.03, Pnoninferiority< 0.0001). Cardiac death, myocardial infarction, and stent thrombosis rates were similar between groups. Angiographic follow-up was available in 104 patients (97.2% of those enrolled in the angiographic substudy) and 128 (94.1%) lesions. At 13months, the powered secondary endpoint of mean in-stent late lumen loss was 0.149 ± 0.263mm for BP-SES and 0.327 ± 0.463mm for control (least squares mean difference:-0.178; 90%CI:-0.2943 to-0.0632; Pnoninferiority< 0.0001). The optical coherence tomography substudy included 37 patients (42 lesions) with no difference in mean neointimal hyperplasia thickness between groups at 13months (Pnoninferiority=0.01). The biodegradable polymer sirolimus-eluting stent was noninferior to currently used second-generation DES with regard to TLF at 1 year. (Firehawk® Rapamycin Target Eluting Coronary Stent North American Trial; NCT04562532).

Covered stent deployment for a recurrent cervical internal carotid artery aneurysm referencing angioscopy: illustrative case.

Extracranial carotid artery aneurysms (ECAAs) are rare, and treatment guidelines are lacking. Few reports on endovascular treatments performed for ECAAs exist. A 73-year-old woman with a left giant cervical internal carotid artery aneurysm was treated with overlapping closed-cell stents. The aneurysm regrew 1 year after the treatment, and then a covered stent was deployed. Angioscopy was performed to confirm neointimal development to determine the appropriate stent position before the retreatment, and it revealed that the stent struts were embedded in thick neointima for the most part but that the neointima was thin around the aneurysm neck. Multiple holes connecting to the aneurysm were observed between the stent struts. A covered stent overlapped inside the closed-cell stents, and blood flow into the aneurysm completely disappeared. When deploying the covered stent for recurrent aneurysms, angioscopy is useful for confirming neointimal development and determining the appropriate stent length and position. Angioscopic observations suggest that using stents with a higher mesh density and smaller pore size can reduce the neck hole size of the aneurysm and may achieve complete occlusion of the aneurysm. https://thejns.org/doi/10.3171/CASE24383.

Restoration of ARA metabolic disorders in vascular smooth muscle cells alleviates intimal hyperplasia

Intimal hyperplasia (IH) is an innegligible issue for patients undergoing interventional therapy. The proliferation and migration of vascular smooth muscle cells (VSMCs) induced by platelet-derived growth factor-BB (PDGF-BB) are critical events in the development of IH. While the exact mechanism and effective target for IH needs further investigation. Metabolic disorders of arachidonic acid (ARA) are involved in the occurrence and progression of various diseases. In this study, we found that the expressions of soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) were significantly increased in the VSMCs during balloon injury-induced IH. Then, we employed a COX-2/sEH dual inhibitor PTUPB to increase the concentration of epoxyeicosatrienoic acids (EETs) while prevent the release of pro-inflammatory prostaglandins. Results showed that PTUPB treatment significantly reduced neointimal thickening induced by balloon injury in rats in vivo and inhibited PDGF-BB-induced proliferation and migration of VSMCs in vitro. Our results showed that PTUPB may reverse the phenotypic transition of VSMCs by inhibiting Pttg1 expression. In conclusion, we found that the dysfunction of ARA metabolism in VSMCs contributes to IH, and the COX-2/sEH dual inhibitor PTUPB attenuates IH progression by reversing the phenotypic switch in VSMC through the Sirt1/Pttg1 pathway.

In vivo biocompatibility of a new hydrophobic coated Al/Al2O3 nanowire surface on stents

BackgroundIntima proliferation and in-stent restenosis is a challenging situation in interventional treatment of small vessel obstruction. Al/Al2O3 nanowires have been shown to accelerate vascular endothelial cell proliferation and migration in vitro, while suppressing vascular smooth muscle cell growth. Moreover, surface modification of Al/Al2O3 nanowires with poly[bis(2,2,2-trifluoromethoxy)phosphazene (PTFEP) coating enables further advantages such as reduced platelet adhesion. Therefore, the study's goal was to compare the biocompatibility of novel Al/Al2O3 + PTFEP coated nanowire bare-metal stents to uncoated control stents in vivo using optical coherence tomography (OCT), quantitative angiography and histomorphometric assessment. Methods15 Al/Al2O3 + PTFEP coated and 19 control stents were implanted in the cervical arteries of 9 Aachen minipigs. After 90 days, in-stent stenosis, thrombogenicity, and inflammatory response were assessed. Scanning electron microscopy was used to analyse the stent surface. ResultsOCT analysis revealed that neointimal proliferation in Al/Al2O3 + PTFEP coated stents was significantly reduced compared to control stents. The neointimal area was 1.16 ± 0.77 mm2 in Al/Al2O3 + PTFEP coated stents vs. 1.98 ± 1.04 mm2 in control stents (p = 0.004), and the neointimal thickness was 0.28 ± 0.20 vs. 0.47 ± 0.10 (p = 0.003). Quantitative angiography showed a tendency to less neointimal growth in coated stents. Histomorphometry showed no significant difference between the two groups and revealed an apparent inflammatory reaction surrounding the stent struts. ConclusionsAt long-term follow-up, Al/Al2O3 + PTFEP coated stents placed in peripheral arteries demonstrated good tolerance with no treatment-associated vascular obstruction and reduced in-stent restenosis in OCT. These preliminary in vivo findings indicate that Al/Al2O3 + PTFEP coated nanowire stents may have translational potential to be used for the prevention of in-stent restenosis.

Inhibition of endothelial-to-mesenchymal transition in a large animal preclinical arteriovenous fistula model leads to improved remodelling and reduced stenosis.

Vein grafts are used for many indications, including bypass graft surgery and arteriovenous fistula (AVF) formation. However, patency following vein grafting or AVF formation is suboptimal for various reasons, including thrombosis, neointimal hyperplasia, and adverse remodelling. Recently, endothelial-to-mesenchymal transition (EndMT) was found to contribute to neointimal hyperplasia in mouse vein grafts. We aimed to evaluate the clinical potential of inhibiting EndMT and developed the first dedicated preclinical model to study the efficacy of local EndMT inhibition immediately prior to AVF creation. We first undertook pilot studies to optimize the creation of a femoral AVF in pigs and verify that EndMT contributes to neointimal formation. We then developed a method to achieve local in vivo SMAD3 knockdown by dwelling a lentiviral construct containing SMAD3 shRNA in the femoral vein prior to AVF creation. Next, in Phase 1, six pigs were randomized to SMAD3 knockdown or control lentivirus to evaluate the effectiveness of SMAD3 knockdown and EndMT inhibition 8 days after AVF creation. In Phase 2, 16 pigs were randomized to SMAD3 knockdown or control lentivirus and were evaluated to assess longer-term effects on AVF diameter, patency, and related measures at 30 days after AVF creation. In Phase 1, compared with controls, SMAD3 knockdown achieved a 75% reduction in the proportion of CD31+ endothelial cells co-expressing SMAD3 (P < 0.001) and also a significant reduction in the extent of EndMT (P < 0.05). In Phase 2, compared with controls, SMAD3 knockdown was associated with an increase in the minimum diameter of the venous limb of the AVF (1.56 ± 1.66 vs. 4.26 ± 1.71 mm, P < 0.01) and a reduced degree of stenosis (P < 0.01). Consistent with this, neointimal thickness was reduced in the SMAD3 knockdown group (0.88 ± 0.51 vs. 0.45 ± 0.19 mm, P < 0.05). Furthermore, endothelial integrity (the proportion of luminal cells expressing endothelial markers) was improved in the SMAD3 knockdown group (P < 0.05). EndMT inhibition in a preclinical AVF model by local SMAD3 knockdown using gene therapy led to reduced neointimal hyperplasia, increased endothelialization, and a reduction in the degree of AVF stenosis. This provides important proof of concept to pursue this approach as a clinical strategy to improve the patency of AVFs and other vein grafts.

Assessment of Effectiveness of the Algorithm for Automated Quantitative Analysis of Metallic Strut Tissue Short-Term Coverage with Intravascular Optical Coherence Tomography.

Background: Due to its high resolution, optical coherence tomography (OCT) is the most suitable modality for neointimal coverage assessments. Evaluation of stent healing seems crucial to accurately define their safety profile since delayed healing is connected with stent thrombosis. This study aimed to present an algorithm for automated quantitative analysis of stent strut coverage at the early stages of vessel healing in intravascular OCT. Methods: A set of 592 OCT frames from 24 patients one month following drug-eluting stent implantation was used to assess the algorithm's effectiveness. Struts not covered on any side or covered but only on one side were categorized as uncovered. The algorithm consists of several key steps: preprocessing, vessel lumen segmentation, automatic strut detection, and measurement of neointimal thickness. Results: The proposed algorithm proved its efficiency in lumen and stent area estimation versus manual reference. It showed a high positive predictive value (PPV) (89.7%) and true positive rate (TPR) (91.4%) in detecting struts. A qualitative assessment for covered and uncovered struts was characterized by high TPR (99.1% and 80%, respectively, for uncovered and covered struts) and PPV (77.3% and 87%). Conclusions: The proposed algorithm demonstrated good agreement with manual measurements. Automating the stent coverage assessment might facilitate imaging analysis, which might be beneficial in experimental and clinical settings.

Preclinical Direct Endoluminal Assessment of Endothelialization After Flow Diversion With Microangioscopy

Background Direct endoluminal imaging, such as with our previously described microangioscope, is an emerging adjunct in endovascular cerebral aneurysm management that enables clinicians to delineate between thrombi and visualize neoepithelialization after stent placement with high resolution. The present study sought to study flow diversion in vivo under direct endoluminal imaging, and to validate our findings with histopathology. Methods In a rabbit model, we implanted each left common carotid artery with a shielded flow diverter (FD) (Medtronic Pipeline Vantage) and nonshielded FD (Medtronic Pipeline Flex) in the right common carotid artery. We studied 9 animals in 3 groups: (1) no periprocedural antiplatelet therapy, (2) aspirin 81 mg daily, and (3) aspirin 81 mg and clopidogrel 75 mg daily. FD thrombosis, stenosis, malapposition, and neoepithelialization were all evaluated by diagnostic cerebral angiography and microangioscopy after 30 days. Diagnostic cerebral angiography and angioscopic video were analyzed by independent evaluators and compared with histopathologic analysis. Results In the aspirin and dual antiplatelet therapy groups, there were no significant observed differences in stent thrombosis, stenosis, malapposition, or neoepithelialization between the shielded and non‐shielded FD groups. There was significantly more thrombus formation in Group 1. Neointimal thickness as measured by the microangioscope was highly correlated with histology (r = 0.72; P = 0.016). Interrater agreement of microangioscope videos was highest for FD thrombosis and stenosis. Conclusion In‐stent thrombosis, stenosis, malapposition, and neopithelialization demonstrated no significant difference between shielded and non‐shielded FDs. Microangioscopy measurements for neointimal thickness were highly correlated with pathology and may be a helpful adjunct to diagnostic cerebral angiography in FD follow‐up.

Abstract 3143: Computational Modeling Of Non-homeostatic Changes Within An Arterial-venous Fistula System Using In Vivo Validation To Understand Mechanical Causes Of Fistula Failure

Introduction: Arteriovenous fistula (AVF) failure is a clinical problem for end stage renal patients seeking durable long term dialysis access. AVF failure is not fully understood, but linked to neointimal hyperplasia (NH). Understanding the hemodynamic factors that may trigger NH response is important for minimizing this clinical problem. Methods: A validated murine AVF model defined the geometry and boundary conditions for the computational model. Anesthetized mice underwent laparotomy and aorta-IVC puncture. Ultrasound specified blood flow velocity within the vessels. In vivo CT angiography scans were segmented using 3D software (Simpleware ScanIP) to establish global geometry which was imported into Xflow, a fluid dynamics simulation software. Velocity, static pressure, and turbulence were averaged along the length of the vein above and below the fistula in this model, a stenotic vein model, and a stenotic fistula model. Results: Velocity and turbulence significantly increases in the peri-fistula vein and dramatically increases in systole phase. Velocity, turbulence, and static pressure peak in the stenotic vein. When the fistula is stenosed, native flow is restored. Conclusions: The presence of AVF dramatically changes the hemodynamics of the native vein. Increased velocity and turbulence in the peri-fistula vein are significant and peak in systole. Venous stenosis substantially strains the system, demonstrated by the high static pressures proximal to the stenosis. The gradients of high turbulence directly correlate with in vivo histology measurements of neointimal hyperplasia thickness changes that have been previously reported. These results may be used to predict how the underlying hemodynamics within a fistula system preclude biological responses from the tissue. We conclude that non-homeostatic hemodynamics, namely increased venous velocity, turbulence, and static pressure may be a potential trigger for NH and ultimately fistula failure.

Leukotriene B4: A potential mediator and biomarker for cardiac allograft vasculopathy

BackgroundCardiac allograft vasculopathy (CAV) remains the leading cause of long-term graft failure and mortality after heart transplantation. Effective preventive and treatment options are not available to-date, largely because underlying mechanisms remain poorly understood. We studied the potential role of leukotriene B4 (LTB4), an inflammatory lipid mediator, in development of CAV. MethodsWe used an established pre-clinical rat CAV model to study the role of LTB4 in CAV. We performed syngeneic and allogeneic orthotopic aortic transplantation, after which neointimal proliferation was quantified. Animals were then treated with Bestatin, an inhibitor of LTB4 synthesis, or vehicle control for 30 days post-transplant, and evidence of graft CAV was determined by histology. We also measured serial LTB4 levels in a cohort of 28 human heart transplant recipients with CAV, 17 matched transplant controls without CAV, and 20 healthy non-transplant controls. ResultsWe showed that infiltration of the arterial wall with macrophages leads to neointimal thickening and a rise in serum LTB4 levels in our rat model of CAV. Inhibition of LTB4 production with the drug Bestatin prevents development of neointimal hyperplasia, suggesting that Bestatin may be effective therapy for CAV prevention. In a parallel study of heart transplant recipients, we found non-significantly elevated plasma LTB4 levels in patients with CAV, compared to patients without CAV and healthy, non-transplant controls. ConclusionsThis study provides key evidence supporting the role of the inflammatory cytokine LTB4 as an important mediator of CAV development, and provides preliminary data suggesting the clinical benefit of Bestatin for CAV prevention.

158 Preclinical Direct Endoluminal Assessment of Endothelialization After Flow Diversion With Microangioscopy

INTRODUCTION: Endoluminal imaging (ELI) is an emerging adjunct in endovascular cerebral aneurysm management. Indirect ELI, as with optical coherence tomography, may be useful in detecting malapposition after flow diversion (FD). Direct ELI technologies, such as with our previous described microangioscope, have been shown to be able to delineate between different thrombi and visualize neoepithelialization after stent placement with high resolution. METHODS: In a rabbit model we implanted each left common carotid artery (CCA) with a shielded FD (Medtronic Pipeline Vantage) and non-shielded FD (Medtronic Pipeline Flex) in the right CCA. We studied 9 animals in 3 groups: 1) no periprocedural antiplatelet therapy, 2) aspirin 81 mg daily, 3) aspirin 81 mg and clopidogrel 75 mg daily. FD thrombosis, stenosis, malapposition, and neoepithelialization were all evaluated by diagnostic cerebral angiography (DSA) and microangioscopy after 30 days. DSA and angioscopic video were analyzed by independent evaluators and compared with histopathologic analysis. RESULTS: In the aspirin and DAPT groups, there were no significant observed differences in stent thrombosis, stenosis, malapposition, or neoepithelialization between the shielded and non-shielded FDs in each rabbit as measured by histologic analysis. There was significantly more thrombus formation in Group 1. Neointimal thickness as measured by the microangioscope was highly correlated with histology (r = 0.72, p = 0.016). Inter-rater agreement of microangioscope videos was highest for FD thrombosis and stenosis. CONCLUSIONS: There were no significant differences between in-stent thrombosis, stenosis, malapposition, or neopithelialization between shielded and non-shielded FDs. Microangioscopy measurements for neointimal thickness were highly correlated with pathology, and thus may be a helpful adjunct to DSA in FD follow-up.

Impact of baseline yellow plaque assessed by coronary angioscopy on vascular response after stent implantation

BackgroundThe relationship between baseline yellow plaque (YP) and vascular response after stent implantation has not been fully investigated. MethodsThis was a sub-analysis of the Collaboration-1 study (multicenter, retrospective, observational study). A total of 88 lesions from 80 patients with chronic coronary syndrome who underwent percutaneous coronary intervention were analyzed. Optical coherence tomography (OCT) and coronary angioscopy (CAS) were serially performed immediately and 11 months after stent implantation. YP was defined as the stented segment with yellow or intensive yellow color assessed by CAS. Neoatherosclerosis was defined as a lipid or calcified neointima assessed by OCT. OCT and CAS findings at 11 months were compared between lesions with baseline YP (YP group) and lesions without baseline YP (Non-YP group). ResultsBaseline YP was detected in 37 lesions (42 %). OCT findings at 11 months showed that the incidence of neoatherosclerosis was significantly higher in the YP group (11 % versus 0 %, p = 0.028) and mean neointimal thickness tended to be lower (104 ± 43 μm versus 120 ± 48 μm, p = 0.098). CAS findings at 11 months demonstrated that the dominant and minimum neointimal coverage grades were significantly lower (p = 0.049 and P = 0.026) and maximum yellow color grade was significantly higher (p < 0.001) in the YP group. ConclusionsBaseline YP affected the incidence of neoatherosclerosis as well as poor neointimal coverage at 11 months after stent implantation.

Silver Ion Decreases Foreign Body Reaction and Venous Neointimal Hyperplasia through the Inhibition of Interleukin-33 Expression

Introduction: Vascular prosthetic grafts are widely used in vascular surgery; however, graft infection remains a major concern. Silver-coated vascular grafts have demonstrated anti-infection properties in clinical settings; however, whether the silver irons influence foreign body reaction or neointimal hyperplasia remains unclear. Methods: Sodium alginate and hyaluronic acid (SA/HA) hydrogel patches loaded with rhodamine, with or without silver, were fabricated. Patches were implanted in the subcutaneous or abdominal cavity and inferior vena cava of rats. Samples were harvested on day 14 and examined via immunohistochemical and immunofluorescence analyses. Results: Silver hydrogel was found to decrease the foreign body reaction; after subcutaneous and abdominal cavity implantation in rats, the capsule was found to be thinner in the silver hydrogel group than in the control hydrogel group. The silver hydrogel group had fewer CD68-positive cells and proliferating cell nuclear antigen and interleukin-33 (IL-33) dual-positive cells than the control hydrogel group. Additionally, the silver hydrogel patch reduced the neointimal thickness after patch venoplasty in rats, and the number of IL-33- and IL-1β-positive cells was lower than that in the control patch. Conclusion: Silver-loaded SA/HA hydrogel patches decreased the foreign body reaction and venous neointimal hyperplasia in rats by the inhibition of IL-33 expression.

Spatial multiomics of arterial regions from cardiac allograft vasculopathy rejected grafts reveal novel insights into the pathogenesis of chronic antibody-mediated rejection

Cardiac allograft vasculopathy (CAV) causes late graft failure and mortality after heart transplantation. Donor-specific antibodies (DSAs) lead to chronic endothelial cell injury, inflammation, and arterial intimal thickening. In this study, GeoMx digital spatial profiling was used to analyze arterial areas of interest (AOIs) from CAV+DSA+ rejected cardiac allografts (N = 3; 22 AOIs total). AOIs were categorized based on CAV neointimal thickening and underwent whole transcriptome and protein profiling. By comparing our transcriptomic data with that of healthy control vessels of rapid autopsy myocardial tissue, we pinpointed specific pathways and transcripts indicative of heightened inflammatory profiles in CAV lesions. Moreover, we identified protein and transcriptomic signatures distinguishing CAV lesions exhibiting low and high neointimal lesions. AOIs with low neointima showed increased markers for activated inflammatory infiltrates, endothelial cell activation transcripts, and gene modules involved in metalloproteinase activation and TP53 regulation of caspases. Inflammatory and apoptotic proteins correlated with inflammatory modules in low neointima AOIs. High neointima AOIs exhibited elevated TGFβ-regulated transcripts and modules enriched for platelet activation/aggregation. Proteins associated with growth factors/survival correlated with modules enriched for proliferation/repair in high neointima AOIs. Our findings reveal novel insight into immunological mechanisms mediating CAV pathogenesis.