Neointimal Thickness Research Articles

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 arterio-venous fistula model leads to improved remodeling and reduced stenosis.

Vein grafts are used for many indications, including bypass graft surgery and arterio-venous fistula (AVF) formation. However, patency following vein grafting or AVF formation is suboptimal for various reasons, including thrombosis, neointimal hyperplasia and adverse remodeling. 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, 6 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 to 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 to controls, SMAD3 knockdown was associated with an increase in the minimum diameter of the venous limb of the AVF (1.56±1.66 versus 4.26±1.71mm, 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 versus 0.45±0.19mm, 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.

Comparison of the “Late Catch-Up” Phenomenon Between BuMA Supreme and XIENCE Stents Through Serial Optical Coherence Tomography at 1–2 Month and 2 Year Follow-Ups: A Multicenter Study

Objectives: This study was aimed at comparing the “late catch-up” phenomenon between the BuMA Supreme bioresorbable polymer sirolimus-eluting stent and the XIENCE stent through serial optical coherence tomography (OCT) at within 2 months and 2 year follow-ups. Methods: A total of 49 of 75 patients from the PIONEER-II study were enrolled in a 2 year OCT follow-up study; 44 patients with 50 lesions were included in the statistical analysis. The primary endpoints were neointimal thickness and late luminal loss (LLL) after stent implantation. Results: The stenosis diameter, and minimum in-stent or in-segment diameter, did not significantly differ between the BuMA Supreme and XIENCE arms at within 2 months and 2 year follow-ups. The strut neointimal coverage and thickness were greater in the BuMA group than the XIENCE group at the 1 and 2 month follow-ups (P = 0.044 and P = 0.010, respectively) but not at the 2 year OCT follow-up. Neither early luminal loss at the within 2 months follow-up (P = 0.849) nor LLL at the 2 year OCT follow-up (P = 0.613) showed differences between device arms. No significant differences in imaging and clinical endpoints were observed between device arms at follow-up. Conclusions: The BuMA Supreme stent’s faster re-endothelization with no “late catch-up” phenomenon has potential advantages over the XIECE stent for patients with coronary artery disease and high bleeding risk because it decreases the duration of dual antiplatelet therapy.

Effects of exenatide on coronary stent’s endothelialization in subjects with type 2 diabetes: a randomized controlled trial. The Rebuild study

BackgroundSubjects with type 2 diabetes (T2D) have a higher risk of in-stent restenosis and stent thrombosis. The activation of the glucagon-like peptide-1 receptor (GLP-1R) has been suggested to induce several effects on the vasculature that may reduce the risk of stent failure following an angioplasty. The aim of this study is to evaluate the effect of the GLP-1R agonist exenatide on endothelialization of a modern drug-eluting stent (DES) in subjects with T2D.Methods38 subjects with T2D who were eligible for revascularization with implantation of DES were randomized to treatment with exenatide (once weekly) plus standard treatment, or to standard treatment alone. After 12 weeks, a new coronary angiography was performed to evaluate the percentage of strut coverage (primary endpoint) and the presence of neo-atherosclerosis by optical coherence tomography. This study was approved by the Stockholm’s Ethical Review Board.ResultsThe two groups were well balanced regarding baseline clinical characteristics. Strut coverage was 95% (88.7–98.5%) in the exenatide group and 91.4% (88.8–98.5%) in the control group (p = 0.692). There were no significant differences between groups neither in the thickness of neo-intima (0.2 mm in both groups, p = 0.471), nor the maximal in-stent obstruction by neo-intima (15.5% in exenatide group vs 14.7% in control group, p = 0.801). No significant differences were detected in the rate of target lesion revascularization between groups (p = 0.224).ConclusionTwelve weeks treatment with exenatide did not lead to a significantly better stent coverage in people with T2D. No significant differences in the occurrence of neo-atherosclerosis were detected between groups.Trial registration: The study was registered at www.clinicaltrials.gov (Rebuild Study, NCT02621489).

Comparison of endothelial shear stress between ultrathin strut bioresorbable polymer drug-eluting stent vs durable-polymer drug-eluting stent post-stent implantation: An optical coherence tomography substudy from BIOFLOW II

BackgroundRecent clinical data indicate a different performance of biodegradable polymer (BP)-drug eluting stent (DES) compared to durable polymer (DP)-DES. Whether this can be explained by a beneficial impact of BP-DES stent design on the local hemodynamic forces distribution remains unclear. ObjectivesTo compare endothelial shear stress (ESS) distribution after implantation of ultrathin (us) BP-DES and DP-DES and examine the association between ESS and neointimal thickness (NIT) distribution in the two devices at 9 months follow up. Methods and resultsWe retrospectively identified patients from the BIOFLOW II trial that had undergone OCT imaging. OCT data were utilized to reconstruct the surface of the stented segment at baseline and 9 months follow-up, simulate blood flow, and measure ESS and NIT in the stented segment. The patients were divided into 3 groups depending on whether DP-DES (N = 8, n = 56,160 sectors), BP-DES with a stent diameter of >3 mm (strut thickness of 80 μm, N = 6, n = 36,504 sectors), or BP-DES with a stent diameter of ≤3 mm (strut thickness of 60 μm, N = 8, n = 50,040 sectors) were used for treatment. The ESS, and NIT distribution and the association of these two variables were estimated and compared among the 3 groups. ResultsIn the DP-DES group mean NIT was 0.18 ± 0.17 mm and ESS 1.68 ± 1.66 Pa; for the BP-DES ≤3 mm group the NIT was 0.17 ± 0.11 mm and ESS 1.49 ± 1.24 Pa and for the BP-DES >3 mm group 0.20 ± 0.23 mm and 1.42 ± 1.24 Pa respectively (p < 0.001 for both NIT and ESS comparisons across groups). A negative correlation between NIT and baseline ESS was found, the correlation coefficient for all the stented segments was −0.33, p < 0.001. ConclusionIn this OCT sub-study of the BIOFLOW II trial, the NIT was statistically different between groups of patients treated with BP-DES and DP-DES. In addition, regions of low ESS were associated with increased NIT in all studied devices.

Effects on re-endothelialisation with Bydureon treatment add on to insulin versus insulin alone, both in combination with metformin in type 2 diabetic subjects: Rebuild study

Abstract Background Patients with type 2 diabetes (T2D) have a higher risk of in-stent restenosis and stent thrombosis following a percutaneous coronary intervention1. The key mechanism for preventing these events after stenting is a restored and well-functioning neo-endothelium2. Several large, randomized trials have shown cardioprotective effect of Glucagon Like Pepetide-1 receptor (GLP-1R) agonists therapy lowering the risk of major adverse cardiovascular events. In addition, activation of GLP-1R has been suggested to induce several effects on the vasculature3 that may reduce not only the risk of atherosclerosis progression, but even the risk of stent failure following an angioplasty. Purpose To evaluate the potential beneficial effect of the GLP-1R agonist Bydureon in the endothelialisation of modern drug-eluting stents (DES) in patients with T2D. Methods 38 subjects with T2D and coronary artery disease who were eligible for revascularisation with implantation of DES were included and randomized to either treatment with Bydureon (once weekly) over the standard treatment, or to standard treatment alone. After 12 weeks, a new coronary angiography was performed to evaluate the coverage of the DES and the presence of neo-atherosclerosis by optical coherence tomography. The main outcome was the percentage of stent coverage at 12 weeks. Descriptive data is shown as median (percentile 25th- 75th). Results The two groups were well balanced regarding baseline clinical characteristics (Table). Neo-intimal coverage could be assessed in all 33 subjects that completed follow-up. DES coverage was 95% (88.7-98.5%) in the Bydureon group and 91.4% (88.8-98.5%) in the Control group (p=0.692). There were no significant differences between groups neither in the thickness of neo-intima (0.2 mm in both groups, p=0.471), nor the maximal in-stent obstruction by neo-intima (15.5% in Bydureon group vs 14.7% in Control group, p= 0.801). Weight decrease was greater in Bydureon group compared to Control group (-7.8 kg vs +0.14 kg, p=0.014), and so was also HbA1c reduction (-11.4 mmol/mol vs -4.7 mmol/mol, p=0.001). No significant differences were detected on the rate of target lesion revascularisation between groups (p=0.224). Conclusion Twelve weeks treatment with Bydureon did not lead to a significantly better stent coverage in patients with T2D. No significant differences in the occurrence of neo-atherosclerosis were detected between groups.Table:Baseline clinical characteristicsImage:Diagram of Methods and Results

Vascular healing of Combo plus stents in patients with acute coronary syndrome

Abstract Background The Combo stent has an abluminal sirolimus-eluting coating composed of a biodegradable polymer to form a drug-eluting stent platform. Sirolimus release is completed in 30 days, and the biodegradable polymer disappears within 90 days. This dual therapy approach aims for neointimal suppression while retaining the endothelial progenitor cell–capturing prohealing benefits enabling rapid endothelialization. However, in patients with acute coronary syndrome (ACS), early vascular healing after COMBO stent implantation remains unknown. Purpose The aim of this study is to elucidate the early phase vascular responses in patients with ACS after COMBO stent implantation at 1 month and 6 months follow-up by using optical coherence tomography (OCT). Methods Twenty-eight patients who underwent primary percutaneous coronary intervention (PCI) for AMI with COMBO stent between March 2020 and July 2020 were examined. All patients received follow-up OCT at 1 and 6 months after primary PCI. For assessment of each strut, OCT images were analyzed at 1.0-mm intervals throughout the stented segment. The degree of strut coverage by OCT were measured both 1 month and 6 months. Results The neointimal thickness were 0.110 ± 0.036 mm at 1 months and 0.217 ±0.083 mm at 6 months (P&amp;lt; 0.001). The median rate of any covered struts was 40.2% at 1 month and 89.5% at 6 months (P&amp;lt; 0.001). The median rate of definite uncovered struts was 14.4% at 1 month and 0.7% at 6 months (P&amp;lt; 0.001). Major adverse cardiac events (MACE) were limited to two target vessel failure without target lesion revascularization. No definite or probable stent thrombosis was noted. Conclusions In patients with MI, the COMBO stent is associated with a high degree of neointimal strut coverage at 1 monthfs. Furthermore, almost complete vascular healing at 6 months is observed. These findings may have impact on the duration of dual anti-platelet therapy in patients with MI who underwent PCI using COMBO stent.

Abstract 14696: Blockade of CD47 Using a Novel Anti-CD47 Molecule, BRB-002, Attenuates Atherosclerosis in an ApoE Mouse Model

Atherosclerosis is characterized by the deposition of lipoproteins in the vessel wall leading to inflammatory response, neointimal thickening, and occlusive plaque. Emerging data suggests that the cell surface marker CD47 is upregulated in atherosclerotic lesions. CD47 produces a ‘don’t eat me’ signal that prevents efficient clearance of diseased vascular cells by phagocytes (a process referred to as ‘efferocytosis’), and it has been hypothesized that dysregulated CD47 may contribute to expansion of atherosclerotic lesions by allowing the accumulation of inflammatory debris in the necrotic core. Blockade of CD47 has been shown to reverse this defect in efferocytosis and attenuate atherosclerosis in mouse models. Here, we evaluated the efficacy of BRB-002, a novel hybrid protein biologic inhibitor of CD47, in a mouse model of atherosclerosis. Four-week-old apolipoprotein E-deficient (ApoE -/-) male mice were fed a high fat diet for 12 weeks during which they were treated with BRB-002 at 2.5 mg/kg, BRB-002 at 10 mg/kg, or IgG isotype control (10 mg/kg) three times a week. Animals were monitored by serial measurements of hematologic parameters, pharmacokinetics, and CD47 receptor occupancy. After 12 weeks, mice were injected with a cathepsin B fluorescent probe and then necropsied to examine their descending aortas. Probes of cathepsin B activity have been used to detect atherosclerotic lesions and shown to correlate with areas of active inflammation and plaque burden. BRB-002 was generally well tolerated in ApoE -/- mice with similar hemoglobin, hematocrit, and red blood cell count between groups. Evaluation of aortas by cathepsin B activity showed that animals treated with BRB-002 at both 2.5 mg/kg and 10 mg/kg dose groups showed significantly decreased cathepsin B activity compared to mice treated with isotype control. These results suggest that blocking CD47 with BRB-002 can attenuate inflammation and atherogenesis in mice.

Abstract 17285: Impact of Baseline Yellow Plaque Assessed by Coronary Angioscopy on 11-month Vascular Response After Stent Implantation

Background: In-stent yellow plaque (YP) evaluated by coronary angioscopy (CAS) 1 year after stent implantation is associated with the future adverse cardiac event. However, the impact of baseline YP on vascular response has not been fully investigated. Methods: This was a sub-analysis of the Collaboraiton-1 study (multicenter, retrospective, observational study). A total of 88 lesions from 80 patients with chronic coronary syndrome who underwent percutaneous coronary intervention with polymer-free biolimus A9-coated stent or durable-polymer everolimus-eluting stent implantation were analyzed. Optical coherence tomography (OCT) and 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. Neointimal coverage (NIC) over the stent was classified into 4 grades by CAS: grade 0, stent struts fully visible; grade 1, stent struts bulging into the lumen, although covered; grade 2, stent struts embedded in the neointima, but translucently visible; and grade 3, stent struts fully embedded and invisible. OCT and CAS findings at 11 months were compared between the lesions with baseline YP (YP group) and those without YP (Non-YP group). Results: Baseline YP was detected in 37 lesions (42%). OCT findings at 11 months showed that the incidence of neoatherosclerosis was significantly higher in YP than Non-YP groups (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 finding at 11 months demonstrated that dominant and minimum NIC grades were significantly lower (Figure) and maximum yellow color grade was significantly higher in YP than Non-YP groups. Conclusions: Baseline YP affected the incidence of neoatherosclerosis as well as poor neointimal coverage at 11 months after stent implantation.

FoxO1 is a negative regulator of neointimal hyperplasia in a rat model of patch angioplasty

Neointimal hyperplasia persists as a barrier following vascular interventions. Forkhead Box O1 (FoxO1) is a transcription factor that possesses a distinctive fork head domain and indirectly contributes to various physiological processes. FoxO1 expression and signaling also impact the energy metabolism of vascular smooth muscle cells, potentially influencing neointimal hyperplasia. Our hypothesis is that FoxO1 inhibits neointimal hyperplasia in a rat patch angioplasty model. Four groups were compared in a rat aorta patch angioplasty model: the control group without treatment, patches coated with AS184286 (a FoxO1 inhibitor) in a PLGA matrix, patches coated with FoxO1 in a PLGA matrix, and patches coated with MLN0905 (a PLK1 inhibitor) in a PLGA matrix. The patches were harvested on Day 14 and subjected to analysis. FoxO1-positive and p-FoxO1 cells were observed after patch angioplasty. The addition of FoxO1 through patches coated with exogenous FoxO1 protein in a PLGA matrix significantly inhibited neointimal thickness (p = 0.0012). The treated groups exhibited significantly lower numbers of CD3 (p = 0.0003), CD45 (p < 0.0001), and PCNA (p < 0.0001)-positive cells. PLK1 is an upstream transcriptional regulator of FoxO1, governing the expression and function of FoxO1. MLN0905 PLGA-coated patches exhibited comparable reductions in neointimal thickness and inflammatory cell accumulation. FoxO1 represents a promising therapeutic strategy for inhibiting neointimal hyperplasia.