Risk factors for instent restenosis of sirolimus-coated stents in coronary intervention for patients with unstable angina.

To investigate the instent restenosis rate of sirolimus-coated stents in percutaneous coronary intervention (PCI) and risk factors for in-stent restenosis, patients with unstable angina (UA) caused by coronary artery stenosis were enrolled, and all clinical and imaging data were analyzed. Among 143 enrolled patients with UA aged 35-83 (mean 60.9 ± 10.0) years enrolled, there were 114 (79.7%) male and 29 (20.3%) female patients. Arterial stenosis was present in one coronary artery in 6 (4.2%) patients, in two coronary arteries in 20 (14.0%) patients, in three arteries in 116 (81.1%), and in four coronary arteries in 1 (0.7%) patient. Stenting was successfully performed in all (100%) patients, and 181 stents were deployed. The quantitative flow ratio (QFR) was 0.92 ± 0.03 (range 0.84-0.96) immediately after stenting, and the TIMI was grade 3 in all patients. The diameter of the stents deployed ranged 2.25-4 mm (mean 3.04 ± 0.44) with a length ranging 10 mm to 104 mm (mean 32.73 ± 15.5). Follow-up angiography was performed in all patients with a duration of 1-92 (mean 15.0 ± 18.8) months. Instent restenosis ≥ 50% occurred in 25 (17.5%) patients. In univariate logistic regression analysis, significant (P < 0.05) risk factors for instent restenosis ≥ 50% were QFR (OR 0.036, 95% CI 0.13-0.97), stent diameter (OR 0.43, 95% CI 0.18-0.92), hypertension (OR 3.16, 95% CI 1.02-9.82), smoking (OR 0.31, 95% CI 0.11-0.89), and neutrophil count (OR 2.22, 95% CI 1.10-5.44). In multivariate analysis, QFR (OR 0.02, 95% CI 0.002-0.19), stent diameter (OR 0.06, 95% CI 0.005-0.59), hypertension (OR 6.75, 95% CI 1.83-35.72) and neutrophil count (OR 276.07, 95% CI 12.32-10,959.95) were significant (P < 0.05) independent risk factors for instent restenosis ≥ 50%. In conclusion, certain instent restenosis rates occurs after the sirolimus-eluted coronary stent deployment for the treatment of coronary artery stenosis in patients with UA, and quantitative flow ratio after stenting, stent diameter, hypertension, and neutrophil count are significant risk factors for instent restenosis of the sirolimus-coated stents in coronary intervention.

Euonymine inhibits in-stent restenosis through enhancing contractile phenotype of vascular smooth muscle cells via modulating the PTEN/AKT/mTOR signaling pathway.

BACKGROUND: Percutaneous coronary intervention (PCI) is an effective treatment for acute myocardial infarction, but the postoperative in-stent re-stenosis (ISR) remains a major risk factor that affects the prognosis of PCI. Clinically, drug-eluting stents (DES) are widely applied to prevent and treat ISR. However, only a few stent coating drugs are currently available for clinical use, including paclitaxel and rapamycin (sirolimus) and their derivatives. These stent-coated drugs have led to a decrease in restenosis rates, but the major adverse outcomes, such as delayed endothelial healing and increased in-stent thrombosis, seriously reduce their therapeutic effects. PURPOSE: Herein, we explored the potential efficacy of Euonymine (Euo), an alkaloid extracted from Tripterygium Hypoglaucum (Levl) Hutch (THH, Lei gong Teng), for the prevention against ISR after PCI. STUDY DESIGN: Our study depicts the potential efficacy of Euo in treating ISR and explores its mechanism with in vitro and in vivo models. METHODS: Primary vascular smooth muscle cells (VSMCs) from the rabbit thoracic aorta were cultured, and the proliferation and migration of VSMCs were monitored. Apoptosis was measured by Transmission Electron Microscopy and TUNEL staining assay. Protein and gene levels were measured to explore the underlying molecular mechanisms. In vivo models of porcine coronary implantation and rabbit carotid balloon injury are used to validate the efficacy of Euo in inhibiting ISR after PCI. RESULTS: With an ox-LDL-injured cell model, we showed that Euo suppressed the proliferation and migration of the rabbit thoracic aorta primary VSMCs, while inducing their apoptosis. We next established a rabbit carotid balloon injury model in which the phosphorylation levels of PI3K and AKT1 (Ser473) as well as mTOR activity were significantly elevated compared to the sham-operated control. These activities were significantly attenuated by the Euo intervention. Additionally, the balloon angioplasty significantly increased the expression of Bcl-2, while decreased the expression of Bax and caspase-3. Euo intervention significantly increased the ratio of Bax/Bcl-2 and the level of caspase-3. Taken together, Euo may enhance the VSMCs contractile phenotype by modulating the PTEN/AKT/mTOR signaling pathway. Furthermore, with two in vivo models, the porcine coronary artery implantation model, and the rabbit carotid balloon injury model, we demonstrated that Euo-eluting stents indeed inhibited ISR after PCI. CONCLUSION: For the first time, this study delineates the potential efficacy of Euo, derived from Tripterygium Hypoglaucum (Levl) Hutch, in ameliorating ISR after PCI with two in vivo models. The phytochemical targets PTEN/AKT/mTOR signaling pathway to increase the contractile phenotype of VSMCs and exerts anti-proliferative, anti-migratory as well as pro-apoptotic effects, thereby inhibiting the ISR.

Cardiotonic Pills® protects from myocardial fibrosis caused by in stent restenosis in miniature pigs.

BACKGROUND: Stent implantation has been increasingly applied for the treatment of obstructive coronary artery disease, which, albeit effective, often harasses patients by in-stent restenosis (ISR). PURPOSE: The present study was to explore the role of compound Chinese medicine Cardiotonic Pills® (CP) in attenuating ISR-evoked myocardial injury and fibrosis. STUDY DESIGN: Chinese miniature pigs were used to establish ISR model by implanting obsolete degradable stents into coronary arteries. Quantitative coronary angiography (QCA) was performed to confirm the success of the model. METHODS: CP was given at 0.2 g/kg daily for 30 days after ISR. On day 30 and 60 after stent implantation, the myocardial infarct and myocardial blood flow (MBF) were assessed. Myocardial histology was evaluated by hematoxylin-eosin and Masson's trichrome staining. The content of ATP, MPO, and the activity of mitochondrial respiratory chain complex Ⅳ were determined by ELISA. Western blot was performed to assess the expression of ATP5D and related signaling proteins, and the mediators of myocardial fibrosis. RESULTS: Treatment with CP diminished myocardial infarct size, retained myocardium structure, attenuated myocardial fibrosis, and restored MBF. CP ameliorated energy metabolism disorder, attenuated TGFß1 up-regulation and reversed its downstream gene expression, such as Smad6 and Smad7, and inhibited the increased expression of MCP-1, PR S19, MMP-2 and MMP-9. CONCLUSION: CP effectively protects myocardial structure and function from ISR challenge, possibly by regulating energy metabolism via inactivation of RhoA/ROCK signaling pathway and inhibition of monocyte chemotaxis and TGF ß1/Smads signaling pathway.

Coronary intravascular brachytherapy for in-stent restenosis: A review of the contemporary literature.

Intracoronary stent restenosis (ISR) is a clinically relevant challenge in the modern era. Heterogeneity in patient- and lesion-specific factors can further compound this clinical challenge. Coronary intravascular brachytherapy (IVBT) was the standard therapeutic approach for ISR prior to the advent of drug-eluting stents (DES). Despite prospective data describing the superiority of DES over IVBT for treating de novo ISR, IVBT remains a treatment option for patients with complex disease. The purpose of this review is to evaluate the historical and contemporary literature surrounding IVBT in order to elucidate its role in modern cardiac care and to describe opportunities for future investigations to improve patient selection. Herein, we provide a review of the contemporary literature describing IVBT as a safe and effective treatment option for patients with recurrent, refractory ISR after multilayer DES and no good surgical or mechanical option. Combination therapy with emerging technologies such as DCBs may further increase efficacy.

miR-126 contributes to the epigenetic signature of diabetic vascular smooth muscle and enhances antirestenosis effects of Kv1.3 blockers.

OBJECTIVES: Restenosis after vessel angioplasty due to dedifferentiation of the vascular smooth muscle cells (VSMCs) limits the success of surgical treatment of vascular occlusions. Type 2 diabetes (T2DM) has a major impact on restenosis, with patients exhibiting more aggressive forms of vascular disease and poorer outcomes after surgery. Kv1.3 channels are critical players in VSMC proliferation. Kv1.3 blockers inhibit VSMCs MEK/ERK signalling and prevent vessel restenosis. We hypothesize that dysregulation of microRNAs (miR) play critical roles in adverse remodelling, contributing to Kv1.3 blockers efficacy in T2DM VSMCs. METHODS AND RESULTS: We used clinically relevant in vivo models of vascular risk factors (VRF) and vessels and VSMCs from T2DM patients. RESUKTS: Human T2DM vessels showed increased remodelling, and changes persisted in culture, with augmented VSMCs migration and proliferation. Moreover, there were downregulation of PI3K/AKT/mTOR and upregulation of MEK/ERK pathways, with increased miR-126 expression. The inhibitory effects of Kv1.3 blockers on remodelling were significantly enhanced in T2DM VSMCs and in VRF model. Finally, miR-126 overexpression confered "diabetic" phenotype to non-T2DM VSMCs by downregulating PI3K/AKT axis. CONCLUSIONS: miR-126 plays crucial roles in T2DM VSMC metabolic memory through activation of MEK/ERK pathway, enhancing the efficacy of Kv1.3 blockers in the prevention of restenosis in T2DM patients.

Honokiol-mesoporous Silica Nanoparticles Inhibit Vascular Restenosis via the Suppression of TGF-ß Signaling Pathway.

INTRODUCTION: The main pathological mechanism of restenosis after percutaneous coronary intervention (PCI) is intimal hyperplasia, which is mainly caused by proliferation and migration of vascular smooth muscle cells (VSMCs). Our previous study found that honokiol (HNK), a small-molecule polyphenol, can inhibit neointimal hyperplasia after balloon injury, but its specific mechanism is still unclear. Moreover, poor water solubility as well as low bioavailability of honokiol has limited its practical use. METHODS: We used mesoporous silica nanoparticles (MSNPs) as a standard substance to encapsulate HNK and then assemble into honokiol-mesoporous silica nanoparticles, and we investigated the effect of these nanoparticles on the process of restenosis after common carotid artery injury in rats. RESULTS: We report a promising delivery system that loads HNK into MSNPs and finally assembles it into a nanocomposite particle. These HNK-MSNPs not merely inhibited proliferation and migration of VSMCs by reducing phosphorylation of Smad3, but also showed a higher suppression of intimal thickening than the free-honokiol-treated group in a rat model of balloon injury. CONCLUSION: To sum up, this drug delivery system supplies a potent nano-platform for improving the biological effects of HNK and provides a promising strategy for preventing vascular restenosis.

Naringenin attenuates carotid restenosis in rats after balloon injury through its anti-inflammation and anti-oxidative effects via the RIP1-RIP3-MLKL signaling pathway.

Vascular restenosis has been proved as the major drawback of percutaneous coronary interventions, which is characterized by neointimal hyperplasia. Naringenin is a kind of natural dihydroflavonoid with a variety of beneficial effects, including anti-oxidative, anti-microbial, anti-cancer and anti-inflammatory properties. However, the effects of naringenin on vascular restenosis remain unclear. This study aimed at investigating the effect and the mechanisms of naringenin on balloon injury (BI)-induced neointimal hyperplasia in the common carotid artery (CCA). BI model of CCA was induced by a 2F Forgarty catheter balloon, and the pathological process of neointimal hyperplasia was noted at 1, 3, 7 and 14 days. Neointimal hyperplasia in CCA increased significantly, especially on day 14 after BI. Subsequently, naringenin (25, 50, 100 mg/kg/d) or volume-matched vehicle were administered to the rats by gavage daily for 14 days. Ultrasound detection and histopathological examination showed that naringenin dose-dependently inhibited BI-induced intimal hyperplasia, as evidenced by reducing imima-media thickness (IMT), neointimal area (NIA), neointimal area/media area (NIA/MA) and neointimal area/internal elastic area (NIA/IELA). Immunohistochemistry revealed that naringenin decreased the expression of proliferating cell nuclear antigen (PCNA) and the cluster of differentiation 163 (CD163). ELISA indicated naringenin significantly reduced the overproduction of IL-1ß and TNF-α. By detecting the activity of superoxide dismutase and the level of malondialdehyde and glutathione, we found that naringenin attenuated BI-induced oxidative stress. Additionally, RT-qPCR demonstrated that receptor-interacting protein 1 (RIP1), RIP3 and mixed lineage kinase domain-like (MLKL) mRNA expression were further down-regulated by naringenin treatment. These results suggested that naringenin can suppress BI-induced vascular neointimal hyperplasia through anti-inflammation and anti-oxidative stress, which may be related to the regulation of RIP1-RIP3-MLKL signaling pathway.

Linagliptin protects rat carotid artery from balloon injury and activates the NRF2 antioxidant pathway.

Percutaneous coronary intervention (PCI) is main treatment for acute coronary syndrome (ACS). However, restenosis caused by PCI-induced injury influences the outcome of patients. Linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, has been reported to ameliorate intimal hyperplasia post vascular injury. The underlying mechanisms by which linagliptin protects against balloon injury are unclear and require to be explored. Herein, Wistar rats with carotid artery balloon injury were given 1, 2 or 3 mg/kg/day linagliprin for 6 weeks. We found that linagliptin attenuated vascular injury-mediated neointima formation in rats without affecting body weight and blood glucose levels. ELISA results indicated that linagliptin significantly reduced overproduction of cytokines including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and IL-6 post balloon injury. By detecting the level of malondialdehyde (MDA) and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), we found that linagliptin prevented balloon injury-induced oxidative stress. Additionally, linagliptin decreased the level of Kelch ECH-associating protein 1 (KEAP1) compared with injury group. Results of Western blots and electrophoretic mobility shift assay (EMSA) demonstrated that linagliptin augmented nuclear accumulation of nuclear factor-E2-related factor 2 (NRF2) and its binding ability to target genes in rats with balloon injury. Moreover, heme oxygenase-1 (HO-1) and NAD (P) H quinine oxidoreductase 1 (NQO1), two downstream targets of NRF2, were further up-regulated after linagliptin treatment compared with injury group. In conclusion, our data suggest that linagliptin protects carotid artery from balloon injury-induced neointima formation and activates the NRF2 antioxidant pathway.

Fufang-Zhenzhu-Tiaozhi Capsule reduces restenosis via the downregulation of NF-kappaB and inflammatory factors in rabbits.

BACKGROUND: To investigate the effects of a Chinese herbal medicine Fufang-Zhenzhu Tiaozhi Capsule (FTZ) on restenosis and elucidate the mechanism of action. METHODS: A restenosis model was established by balloon rubbing the endothelium of the abdominal aorta followed by high fat diet. Rabbits were divided into blank control group, restenosis group, FTZ group (0.66 mg/kg/day), atorvastatin group (5 mg/kg/day) and FTZ + atorvastatin group (n = 8). Vascular stenosis was analyzed by X-ray. Serum levels of chemokines and cytokines interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-12 (IL-12), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) were measured by ELISA. The levels of NF-κB, IκB-α, P-IκBα, IKK-α, and P-IKKα/ß from injured abdominal arteries were detected by Western blotting. RESULTS: Restenosis was induced successfully via abdominal artery balloon injuries and high fat diet. Restenosis was significantly decreased in FTZ group compared with restenosis group (P < 0.05). FTZ group had markedly reduced serum lipid levels (P < 0.05). In addition, the levels of TNF-α, IL-1, IL-6, IL-8, IL-12, ICAM-1 and MCP-1 decreased by FTZ treatment (P < 0.05). The expression of NF-κB in the atherosclerotic lesions was significantly attenuated in FTZ group (P < 0.05). CONCLUSION: FTZ could reduce restenosis via reducing NF-κB activity and inflammatory factor expression within the atherosclerotic lesion in a rabbit restenosis model. FTZ may be a new therapeutic agent for restenosis.

Effects of Rosuvastatin on Apolipoprotein J in Balloon-Injured Carotid Artery in Rats.

BACKGROUND: Restenosis after percutaneous coronary intervention in coronary heart disease remains an unsolved problem. Clusterin (CLU) (or Apolipoprotein [Apo] J) levels have been reported to be elevated during the progression of postangioplasty restenosis and atherosclerosis. However, its role in neointimal hyperplasia is still controversial. OBJECTIVE: To elucidate the role Apo J in neointimal hyperplasia in a rat carotid artery model in vivo with or without rosuvastatin administration. METHODS: Male Wistar rats were randomly divided into three groups: the control group (n = 20), the model group (n = 20) and the statin intervention group (n = 32). The rats in the intervention group were given 10mg /kg dose of rosuvastatin. A 2F Fogarty catheter was introduced to induce vascular injury. Neointima formation was analyzed 1, 2, 3 and 4 weeks after balloon injury. The level of Apo J was measured by real-time PCR, immunohistochemistry and western blotting. RESULTS: Intimal/medial area ratio (intimal/medial, I/M) was increased after balloon-injury and reached the maximum value at 4weeks in the model group; I/M was slightly increased at 2 weeks and stopped increasing after rosuvastatin administration. The mRNA and protein levels of Apo J in carotid arteries were significantly upregulated after rosuvastatin administration as compared with the model group, and reached maximum values at 2 weeks, which was earlier than in the model group (3 weeks). CONCLUSION: Apo J served as an acute phase reactant after balloon injury in rat carotid arteries. Rosuvastatin may reduce the neointima formation through up-regulation of Apo J. Our results suggest that Apo J exerts a protective role in the restenosis after balloon-injury in rats.

Effects of Rosuvastatin on Apolipoprotein J in Balloon-Injured Carotid Artery in Rats / Efeitos da Rosuvastatina sobre Apolipoproteína J em Artérias de Ratos Lesionadas com Balão

Abstract Background: Restenosis after percutaneous coronary intervention in coronary heart disease remains an unsolved problem. Clusterin (CLU) (or Apolipoprotein [Apo] J) levels have been reported to be elevated during the progression of postangioplasty restenosis and atherosclerosis. However, its role in neointimal hyperplasia is still controversial. Objective: To elucidate the role Apo J in neointimal hyperplasia in a rat carotid artery model in vivo with or without rosuvastatin administration. Methods: Male Wistar rats were randomly divided into three groups: the control group (n = 20), the model group (n = 20) and the statin intervention group (n = 32). The rats in the intervention group were given 10mg /kg dose of rosuvastatin. A 2F Fogarty catheter was introduced to induce vascular injury. Neointima formation was analyzed 1, 2, 3 and 4 weeks after balloon injury. The level of Apo J was measured by real-time PCR, immunohistochemistry and western blotting. Results: Intimal/medial area ratio (intimal/medial, I/M) was increased after balloon-injury and reached the maximum value at 4weeks in the model group; I/M was slightly increased at 2 weeks and stopped increasing after rosuvastatin administration. The mRNA and protein levels of Apo J in carotid arteries were significantly upregulated after rosuvastatin administration as compared with the model group, and reached maximum values at 2 weeks, which was earlier than in the model group (3 weeks). Conclusion: Apo J served as an acute phase reactant after balloon injury in rat carotid arteries. Rosuvastatin may reduce the neointima formation through up-regulation of Apo J. Our results suggest that Apo J exerts a protective role in the restenosis after balloon-injury in rats.

Resumo Fundamento: A reestenose após intervenção coronária percutânea (ICP) após doença coronariana continua um problema não solucionado. Estudos relataram que os níveis de clusterina (CLU), também chamada de apolipoproteína (Apo) J, encontram-se elevados na progressão da reestenose pós-angioplastia e na aterosclerose. Contudo, seu papel na hihperplasia neointimal ainda é controverso. Objetivo: Elucidar o papel da Apo J na hiperplasia neointimal na artéria carótida utilizando um modelo experimental com ratos in vivo, com e sem intervenção com rosuvastatina. Métodos: ratos Wistar machos foram divididos aleatoriamente em três grupos - grupo controle (n = 20), grupo modelo (n = 20), e grupo intervenção com estatina (n = 32). Os ratos no grupo intervenção receberam 10 mg/kg de rosuvastatina. Um cateter Fogarty 2 F foi introduzido para induzir lesão vascular. A formação de neoíntima foi analisada 1, 2, 3 e 4 semanas após lesão com balão. Concentrações de Apo J foram medidas por PCR em tempo real, imuno-histoquímica e western blotting. Resultados: A razão área íntima/média (I/M) aumentou após a lesão com balão e atingiu o valor máximo 4 semanas pós-lesão no grupo modelo; observou-se um pequeno aumento na I/M na semana 2, que cessou após a administração de rosuvastatina. Os níveis de mRNA e proteína da Apo J nas artérias carótidas aumentaram significativamente após administração de rosuvastatina em comparação ao grupo modelo, atingindo o máximo na semana 2, mais cedo em comparação ao grupo modelo (semana 3). Conclusão: A Apo J atuou como reagente de fase aguda após lesão com balão nas artérias carótidas de ratos. A rosuvastatina pode reduzir a formação de neoíntoma por aumento de Apo J. Nossos resultados sugerem que a Apo J exerce um papel protetor na reestenose após lesão com balão em ratos.

Exogenous SERP1 attenuates restenosis by restoring GLP-1 receptor activity in diabetic rats following vascular injury.

The activity of glucagon-like peptide 1 (GLP-1R) is essential for preventing restenosis following vascular injury; however, the mechanism of dysfunctional GLP-1R glycosylation and ways to enhance the activity of GLP-1R on vascular surfaces in diabetic patients are poorly understood. In the present study, we investigated the N-glycosylation level and role of stress-associated endoplasmic reticulum protein 1 (SERP1) in preventing restenosis following carotid injury in diabetic rats. Our results showed that N-glycosylation levels in both rat aortic endothelial cells (RAOECs) and rat vascular smooth muscle cells (VSMCs) decreased gradually following glucose treatment in a concentration dependant manner. Furthermore, co-immunoprecipitation (Co-IP) analyses indicated that SERP1 could interact with GLP-1R in RAOECs and VSMCs. Moreover, SERP1 enhanced GLP-1R N-glycosylation and increased the production of phosphorylated endothelial nitric oxide synthase (eNOS) as well as proliferation of RAOECs. SERP1 also increased phosphorylated adenosine monophosphate activated protein kinase (AMPK) and decreased the migration of VSMCs. Importantly, intima media thickness (IMT) and neointimal hyperplasia were alleviated in the carotid artery of diabetic rats injected with SERP1 following balloon injury. We also found an increase in re-endothelialization and a decrease in VSMC proliferation in the carotid artery of diabetic rats injected with SERP1. In summary, the remarkable effects of SERP1 on reducing restenosis following vascular injury may contribute to future advancements in the treatment of diabetic vascular complications.

Effects of ticagrelor on neointimal hyperplasia and endothelial function, compared with clopidogrel and prasugrel, in a porcine coronary stent restenosis model.

BACKGROUND: Several investigations have been conducted to evaluate the off-target effects of ticagrelor. The aim of the present study was to evaluate the off-target effects of ticagrelor such as neointimal formation and endothelial function after drug-eluting stent implantation in a porcine restenosis model. METHODS: A total of 30 pigs were randomly allocated based on the following P2Y12 inhibitor: (1) clopidogrel 300mg loading plus 75mg maintenance (n=10); (2) prasugrel 60mg loading plus 10mg maintenance (n=10); (3) ticagrelor 180mg loading plus 180mg maintenance (n=10). In each group, zotarolimus-eluting stents were implanted in the proximal portion of the left anterior descending artery and left circumflex artery. One month after stenting, the animals underwent follow-up angiography, endothelial function assessment, optical coherence tomography (OCT) and histopathological analysis. RESULTS: Regarding vasomotor responses to acetylcholine infusion, there were significant vasoconstrictions to maximal acetylcholine infusion in the clopidogrel and prasugrel group compared with those in the ticagrelor group. The mean neointimal area were significantly lower in the ticagrelor group (1.0±0.3 by OCT, 0.9±0.3 by histology), than in the clopidogrel (1.8±0.7, p=0.003, 1.6±0.8, p=0.030) and prasugrel (1.8±0.5, p=0.001, 1.5±0.5, p=0.019) groups. Percentages of moderate to dense peri-strut inflammatory cell infiltration were significantly lower in the ticagrelor group (9.0%) compared with the clopidogrel (17.3%, p<0.001) and prasugrel groups (15.7%, p=0.002). There were no significant differences in all findings between clopidogrel and prasugrel groups. CONCLUSIONS: Compared to clopidogrel and prasugrel, ticagrelor reduced neointimal formation, endothelial dysfunction, and peri-strut inflammation.

Inverse Relationship between Serum VEGF Levels and Late In-Stent Restenosis of Drug-Eluting Stents.

Late in-stent restenosis (ISR) has raised concerns regarding the long-term efficacy of drug-eluting stents (DES). The role of vascular endothelial growth factor (VEGF) in the pathological process of ISR is controversial. This retrospective study aimed to investigate the relationship between serum VEGF levels and late ISR in patients with DES implantation. A total of 158 patients who underwent angiography follow-up beyond 1 year after intervention were included. The study population was classified into ISR and non-ISR groups. The ISR group was further divided according to follow-up duration and Mehran classification. VEGF levels were significantly lower in the ISR group than in the non-ISR group [96.34 (48.18, 174.14) versus 179.14 (93.59, 307.74) pg/mL, p < 0.0001]. Multivariate regression revealed that VEGF level, procedure age, and low-density lipoprotein cholesterol were independent risk factors for late ISR formation. Subgroup analysis demonstrated that VEGF levels were even lower in the very late (≥5 years) and diffuse ISR group (Mehran patterns II, III, and IV) than in the late ISR group (1-4 years) and the focal ISR group (Mehran pattern I), respectively. Furthermore, significant difference was found between diffuse and focal ISR groups. Serum VEGF levels were inversely associated with late ISR after DES implantation.

Stent-mediated gene and drug delivery for cardiovascular disease and cancer: A brief insight.

This review concisely recapitulates the different existing modes of stent-mediated gene/drug delivery, their considerable advancement in clinical trials and a rationale for other merging new technologies such as nanotechnology and microRNA-based therapeutics, in addition to addressing the limitations in each of these perpetual stent platforms. Over the past decade, stent-mediated gene/drug delivery has materialized as a hopeful alternative for cardiovascular disease and cancer in contrast to routine conventional treatment modalities. Regardless of the phenomenal recent developments achieved by coronary interventions and cancer therapies that employ gene and drug-eluting stents, practical hurdles still remain a challenge. The present review highlights the limitations that each of the existing stent-based gene/drug delivery system encompasses and therefore provides a vision for the future with respect to discovering an ideal stent therapeutic platform that would circumvent all the practical hurdles witnessed with the existing technology. Further study of the improvisation of next-generation drug-eluting stents has helped to overcome the issue of restenosis to some extent. However, current stent formulations fall short of the anticipated clinically meaningful outcomes and there is an explicit need for more randomized trials aiming to further evaluate stent platforms in favour of enhanced safety and clinical value. Gene-eluting stents may hold promise in contributing new ideas for stent-based prevention of in-stent restenosis through genetic interventions by capitalizing on a wide variety of molecular targets. Therefore, the central consideration directs us toward finding an ideal stent therapeutic platform that would tackle all of the gaps in the existing technology.

Modelling chemistry and biology after implantation of a drug-eluting stent. Part I: Drug transport.

Drug-eluting stents have been used widely to prevent restenosis of arteries following percutaneous balloon angioplasty. Mathematical modelling plays an important role in optimising the design of these stents to maximise their efficiency. When designing a drug-eluting stent system, we expect to have a sufficient amount of drug being released into the artery wall for a sufficient period to prevent restenosis. In this paper, a simple model is considered to provide an elementary description of drug release into artery tissue from an implanted stent. From the model, we identified a parameter regime to optimise the system when preparing the polymer coating. The model provides some useful order of magnitude estimates for the key quantities of interest. From the model, we can identify the time scales over which the drug traverses the artery wall and empties from the polymer coating, as well as obtain approximate formulae for the total amount of drug in the artery tissue and the fraction of drug that has released from the polymer. The model was evaluated by comparing to in-vivo experimental data and good agreement was found.

Therapeutic Effect of Akt1 siRNA Nanoparticle Eluting Coronary Stent on Suppression of Post-Angioplasty Restenosis.

For effective treatment of restenosis, therapeutic genes are delivered locally from a coated stent at the site of injury, leading to inhibition of smooth muscle proliferation and neo-intimal hyperplasia while promoting re-endothelialization. In a previous study, we delivered Akt1 siRNA nanoparticles (ASNs) from a hyaluronic acid (HA)-coated stent surface to specifically suppress the pro-proliferative Akt1 protein in smooth muscle cells (SMCs). In the present study, therapeutic efficacy was investigated in a rabbit restenosis model after percutaneous implantation of an ASN-immobilized stent in a rabbit iliac artery. Quantitative and qualitative analyses of in-stent restenosis were investigated in an in vivo animal model by micro-CT imaging and SEM observation, respectively. Proliferation status and neo-intima formation of the vascular tissues located near ASN-immobilized stents were analyzed by immunohistochemical staining using anti-Akt1 and anti-Ki67 antibodies and histological analyses, such as hematoxylin and eosin staining and Verhoeff's elastic stain. Re-endothelialization after implantation of an ASN-immobilized stent was also analyzed via immunohistochemistry using an anti-CD31 antibody. To elucidate the molecular mechanism related to reducing SMC proliferation and subsequent inhibition of in-stent restenosis in vivo, protein and mRNA expression of Akt1 and downstream signaling proteins were analyzed after isolating SMC-rich samples from the treated vasculature. The implanted Akt1 siRNA-eluting stent efficiently mitigated in-stent restenosis without any side effects and can be considered a successful substitute to current drug-eluting stents.