The application of tissue-engineered fish swim bladder vascular graft

Small diameter (< 6 mm) prosthetic vascular grafts continue to show very low long-term patency, but bioengineered vascular grafts show promising results in preclinical experiments. To assess a new scaffold source, we tested the use of decellularized fish swim bladder as a vascular patch and tube in rats. Fresh goldfish (Carassius auratus) swim bladder was decellularized, coated with rapamycin and then formed into patches or tubes for implantation in vivo. The rapamycin-coated patches showed decreased neointimal thickness in both the aorta and inferior vena cava patch angioplasty models. Rapamycin-coated decellularized swim bladder tubes implanted into the aorta showed decreased neointimal thickness compared to uncoated tubes, as well as fewer macrophages. These data show that the fish swim bladder can be used as a scaffold source for tissue-engineering vascular patches or vessels.

Mobilization of progenitor cells and vessel healing after implantation of SYNERGY in acute coronary syndrome

This study was aimed to compare the vascular healing process of a SYNERGY stent with that of a PROMUS PREMIER stent in patients with acute coronary syndrome (ACS). In 71 patients with ACS, undergoing coronary stent implantation using the SYNERGY stent (n = 52) or PROMUS PREMIER stent (n = 19), we measured circulating CD34+/CD133+/CD45null cells and CD34+/KDR+ cells and observed vascular healing at the stented sites using optical coherence tomography (OCT) and coronary angioscopy. On the day 7, circulating CD34+/CD133+/CD45null cells increased in SYNERGY group (P < 0.0001), while it did not change in PROMUS group. The CD34+/KDR+ cells also increased in SYNERGY group (P < 0.0001) but less significantly in the PROMUS group (P < 0.05). The OCT-based neointimal thickness (P < 0.0005) and neointimal coverage rate (P < 0.05) at 12 months were greater in SYNERGY group, compared with PROMUS group. The coronary angioscopy-based neointimal coverage grade at 12 months was also greater in SYNERGY group (P < 0.001). In overall patients, the change in CD34+/KDR+ cells on the day 7 correlated with the OCT-based neointimal thickness at 12 months (R = 0.288, P < 0.05). SYNERGY stent seems to have potential advantages over PROMUS PREMIER stent for ACS patients in terms of vascular healing process at the stented sites.

Optical coherence tomography tissue coverage and characterization at six months after implantation of bioresorbable scaffolds versus conventional everolimus eluting stents in the ISAR-Absorb MI trial

Purpose Data regarding vessel healing by optical coherence tomography (OCT) after everolimus-eluting bioresorbable scaffolds (BRS) or everolimus-eluting metallic stent (EES) implantation in acute myocardial infarction (AMI) patients is scarce. We compared OCT findings after BRS or EES implantation in patients with AMI enrolled in a randomized trial. Methods In ISAR-Absorb MI, AMI patients were randomized to BRS or EES implantation, with 6–8 month angiographic follow-up. This analysis includes patients who underwent OCT during surveillance angiography. Tissue characterization was done using grey-scale signal intensity analysis. The association between OCT findings and target lesion failure (TLF) at 2 years was investigated. Results OCT was analyzed in 103 patients (2237 frames, 19,827 struts) at a median of 216 days post-implantation. Of these, 70 were treated with BRS versus 32 with EES. Pre-(92.8 vs. 68.7%, p = 0.002) and post-dilation (51.4 vs. 12.5%, p < 0.001) were more common in BRS as compared to EES. Strut coverage was higher in BRS vs. EES (97.5% vs. 90.9%, p < 0.001). Mean neointimal thickness was comparable in both groups [85.5 (61.9, 124.1) vs. 69.5 (32.7, 127.5) µm, respectively, p = 0.20]. Mature neointimal regions were numerically more common in BRS (43.0% vs. 24.6%; p = 0.35); this difference was statistically significant in ST-elevation myocardial infarction patients (40.9% vs. 21.1%, p = 0.03). At two-years, 8 (7.8%) patients experienced TLF. Mean neointimal area [0.61 (0.21, 1.33) vs. 0.41 (0.11, 0.75) mm2, p = 0.03] and mean neointimal coverage [106.1 (65.2, 214.8) vs. 80.5 (53.5, 122.1) µm, p < 0.01] were higher, with comparable tissue maturity, in lesions with versus without TLF. Conclusions In selected patients who underwent OCT surveillance 6–8 months after coronary intervention for AMI with differing implantation characteristics depending on the device type used, vessel healing was more advanced in BRS compared with EES, particularly in the STEMI subgroup.

Better vascular healing of ultrathin strut biodegradable-polymer sirolimus-eluting stents in patients with acute coronary syndrome

This study aimed to compare the strut coverage between Orsiro ultrathin struts biodegradable polymer sirolimus-eluting stents (O-SES) and Xience thin struts durable polymer everolimus-eluting stents (X-EES) in acute coronary syndrome (ACS) patients using optical coherence tomography (OCT). In BIOSTEMI trial, O-SESs were superior to X-EESs with respect to target lesion failure (TLF) in ACS patients. However, there were few reports comparing intravascular imaging between the two stents in ACS. Between August 2016 and February 2020, 50 lesions from 50 ACS patients who underwent OCT-guided percutaneous coronary intervention (PCI) were enrolled. We compared mid-term vascular healing using OCT between O-SESs and X-EESs at 8-month after stenting. The protocol was approved by the Osaka Rosai Hospiral ethics committee. Among 50 lesions, the X-EES group consisted of 25 lesions and the O-SES of 25 lesions. The percentage of covered strut, the percentage of malapposed strut and mean neointimal thickness at 8-month were evaluated. In the 8-month OCT analysis, the proportion of covered strut was significantly higher in the O-SES group than in in the X-EES group (97.3% vs. 86.0%; p = 0.001). On the other hand, there were no significant differences in the frequency of malapposed strut (0.4% vs 1.0%, p = 0.238). The O-SES group had the tendency of thinner neointima compared to the X-EES group (60µm vs 76µm, p = 0.089). Compared to X-EESs, O-SESs showed better mid-term vascular healing and tended to have thinner neointima in ACS patients. Ultra-thin strut may play a key role in better vascular healing.

Mobilization of Progenitor Cells and Vessel Healing After Implantation of Synergytm in Acute Coronary Syndrome

This study was aimed to compare the vascular healing process of a SYNERGYTM stent with that of a PROMUS PREMIERTM stent in patients with acute coronary syndrome (ACS). In 71 patients with ACS, undergoing coronary stent implantation using the SYNERGYTM stent (n=52) or PROMUS PREMIERTM stent (n=19), we measured circulating CD34+/CD133+/CD45null cells and CD34+/KDR+ cells and observed vascular healing at the stented sites using optical coherence tomography (OCT) and coronary angioscopy. On the day 7, circulating CD34+/CD133+/CD45null cells increased in SYNERGY group (P<0.0001), while it did not change in PROMUS group. The CD34+/KDR+ cells also increased in SYNERGY group (P<0.0001) but less significantly in the PROMUS group (P<0.05). The OCT-based neointimal thickness (P<0.0005) and neointimal coverage rate (P<0.05) at 12 months were greater in SYNERGY group, compared with PROMUS group. The coronary angioscopy-based neointimal coverage grade at 12 months was also greater in SYNERGY group (P<0.001). In overall patients, the change in CD34+/KDR+ cells on the day 7 correlated with the OCT-based neointimal thickness at 12 months (R=0.288, P<0.05). SYNERGYTM stent seems to have potential advantages over PROMUS PREMIERTM stent for ACS patients in terms of vascular healing process at the stented sites.

Endothelial nitric oxide synthase (eNOS) mediates neointimal thickness in arteriovenous fistulae with different anastomotic angles in rats

Background: It is known that the anastomotic angle can influence neointimal hyperplasia and patency in arteriovenous fistulae (AVF). Endothelial nitric oxide synthase (eNOS) is released from the vascular endothelium and can inhibit neointimal hyperplasia. Therefore, here, we aimed to test the hypothesis that the manipulation of eNOS expression could influence neointimal thickness in a rat AVF model with different anastomosis angles. Methods: Rat carotid artery (inflow, CA) and jugular vein (outflow, JV) AVF were created with acute, blunt, or end-to-end (ETE) anastomosis angles. Aspirin was used to increase eNOS expression in the acute angle group, while N(G)-nitro-L-arginine methyl ester (L-name) was used to decrease eNOS expression in the obtuse angle group. The rats were sacrificed on day 21, and tissues were harvested and analyzed histologically and with immunostaining. Results: A larger anastomosis diameter ( p < 0.016) and smaller neointimal area ( p < 0.01) were observed in the obtuse and end-to-end (ETE) groups compared to in the acute group. In the acute angle group, there were more proliferating cell nuclear antigen (PCNA) and α-actin dual-positive cells ( p < 0.0001) and fewer phospho (p)-eNOS-positive endothelial cells ( p < 0.0001) in the neointima than in the obtuse and ETE angle groups. On treating the acute angle and blunt angle groups with aspirin and L-name, respectively, no significant differences in the neointima/lumen rate were observed ( p = 0.6526) between the groups; however, there were fewer von Willebrand factor (vWF) and p-eNOS dual-positive cells in the obtuse angle group treated with L-name ( p = 0.0045). Conclusions: We demonstrated that eNOS plays an important role in neointimal hyperplasia in AVF with different anastomosis angles; further, eNOS could potentially be used as a therapeutic target in patients with AVF in the future.

Ex Vivo assessment of competent strut coverage after coronary stenting by optical coherence tomography

Background In many studies, struts coverage is defined as &gt;0 mm of tissue overlying the stent struts by optical coherence tomography (OCT). However, this definition has never been validated using histology as the “gold standard”. The present study sought to assess the appropriate cut-off value of neointimal thickness of stent strut coverage by OCT using histology. Methods OCT imaging was performed on 39 human coronary arteries with stents from 25 patients at autopsy. A total of 165 cross-sectional images from 46 stents were co-registered with histology. The optimal cut-off value of strut coverage by OCT was determined. Strut coverage by histology was defined as endothelial cells with at least underlying two layers of smooth muscle cells. Considering the resolution of OCT is 10–20 μm, 3 different cut-off values (i.e. at ≥20, ≥40, and ≥60 μm) were assessed. Results A total of 2235 struts were evaluated by histology. Eventually, 1216 struts which were well-matched struts were analyzed in this study. By histology, uncovered struts were observed in 160 struts and covered struts were observed in 1056 struts. The broadly used definition of OCT-coverage which does not consider neointimal thickness yielded a poor specificity of 37.5% and high sensitivity 100%. Of 3 cut-off values, the cut-off value of &gt;40 μm was more accurate as compared to &gt;20 and &gt;60 mm [sensitivity (99.3%), specificity (91.0%), positive predictive value (98.6%), and negative predictive value (95.6%)] Conclusion The most accurate cut-off value was ≥40 μm neointimal thickness by OCT in order to identify stent strut coverage validated by histology. Funding Acknowledgement Type of funding source: None

Healthy Strut Coverage After Coronary Stent Implantation

Background: Struts have been considered as covered when tissue overlying the struts is >0 μm by optical coherence tomography (OCT). However, there is no confirmatory study to validate this definition by histology which is the gold standard. The aim of the present study was to assess the appropriate cutoff value of neointimal thickness of stent strut coverage by OCT with histology confirmation. Methods: We performed ex vivo OCT imaging of human coronary arteries with stents at autopsy. A total of 46 stents in 39 vessels from 25 patients were examined in this study, and a total of 165 cross-sectional images were co-registered with histology to determine the optimal cutoff value for strut coverage by OCT which was defined as luminal endothelial cells with 2 abluminal layers of smooth muscles cells and matrix. Considering the resolution of OCT is 10 to 20 μm, the cutoff values were assessed at ≥20, ≥40, and ≥60 μm. Results: A total of 2235 struts were reviewed by histology, 1216 were considered as well-matched struts which were analyzed in this study. By histology, 160 struts were identified as uncovered, while 1056 struts were covered. The OCT assessment without consideration of neointimal thickness yielded a poor specificity of 37.5% and sensitivity 100%. Of 3 cutoff values, the cutoff value of ≥40 μm yielded the best sensitivity (99.3%), specificity (91.0%), positive predictive value (98.6%), and negative predictive value (95.6%) as compared with ≥20 and ≥60 μm. Conclusions: Neointimal thickness ≥40 μm by OCT yielded the most accurate cutoff value to identify stent strut coverage validated by histology.

Combinatorial therapy of sirolimus and heparin by nanocarrier inhibits restenosis after balloon angioplasty ex vivo

Aim: To develop poly(lactide-co-glycolide)-graft-polyethylenimine (PgP) as a dual drug-delivery carrier for sirolimus (SR) and heparin (Hep) to inhibit restenosis after balloon angioplasty. Materials & methods: SR was loaded in the hydrophobic core and negatively charged Hep complexed with the positively charged hydrophilic shell of PgP. SR- and Hep-loaded PgP was tested on rat aortic smooth muscle cells in vitro and injured porcine coronary arteries after balloon angioplasty ex vivo. Results & conclusion: SR and Hep loading efficiency in PgP were approximately 37 and 82%, respectively. SR- and Hep-loaded PgP treatment decreased smooth muscle cell proliferation up to 14 days post-treatment and decreased proliferation, collagen deposition and neointimal thickness and increased patency in porcine coronary arteries after balloon angioplasty ex vivo.

Everolimus-Eluting Biodegradable Abluminal Coating Stent versus Durable Conformal Coating Stent: Termination of the Inflammatory Response Associated with Neointimal Healing in a Porcine Coronary Model

Objectives. We evaluated the effect of the different carrier systems on early vascular response through histological analysis and scanning electron microscopy using a porcine model. Background. Although Synergy™ and Promus PREMIER™ share an identical stent material and drug elution (everolimus), they use different drug carrier systems: biodegradable abluminal coating polymer or durable conformal coating polymer, respectively. However, data regarding the impact of the different coating systems on vessel healing are currently limited. Methods. Twelve Synergy™ and Promus PREMIER™ were implanted in 12 swine. Histopathological analysis of the stented segments was performed on the 2nd and 14th days after implantation. Morphometric analysis of the inflammation and intimal fibrin content was also performed. Results. On the 2nd day, neointimal thickness, percentage of neointimal area, and inflammatory and intimal fibrin content scores were not significantly different between the two groups. On the 14th day, the inflammatory and intimal fibrin content scores were significantly lower in Synergy™ versus those observed in Promus PREMIER™. In Synergy™, smooth muscle cells were found and the neointimal layers were smooth. In contrast, inflammatory cells were observed surrounding the struts of Promus PREMIER™. Conclusions. These results demonstrate that termination of reactive inflammation is accelerated after abluminal coating stent versus implantation of conformal coating stent.