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1.
Transl Res ; 224: 40-54, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32522668

RESUMO

The modulation of voltage-gated K+ (Kv) channels, involved in cell proliferation, arises as a potential therapeutic approach for the prevention of intimal hyperplasia present in in-stent restenosis (ISR) and allograft vasculopathy (AV). We studied the effect of PAP-1, a selective blocker of Kv1.3 channels, on development of intimal hyperplasia in vitro and in vivo in 2 porcine models of vascular injury. In vitro phenotypic modulation of VSMCs was associated to an increased functional expression of Kv1.3 channels, and only selective Kv1.3 channel blockers were able to inhibit porcine VSMC proliferation. The therapeutic potential of PAP-1 was then evaluated in vivo in swine models of ISR and AV. At 15-days follow-up, morphometric analysis demonstrated a substantial reduction of luminal stenosis in the allografts treated with PAP-1 (autograft 2.72 ± 1.79 vs allograft 10.32 ± 1.92 vs allograft + polymer 13.54 ± 8.59 vs allograft + polymer + PAP-1 3.06 ± 1.08 % of luminal stenosis; P = 0.006) in the swine model of femoral artery transplant. In the pig model of coronary ISR, using a prototype of PAP-1-eluting stent, no differences were observed regarding % of stenosis compared to control stents (31 ± 13 % vs 37 ± 18%, respectively; P = 0.372) at 28-days follow-up. PAP-1 treatment was safe and did not impair vascular healing in terms of delayed endothelialization, inflammation or thrombosis. However, an incomplete release of PAP-1 from stents was documented. We conclude that the use of selective Kv1.3 blockers represents a promising therapeutic approach for the prevention of intimal hyperplasia in AV, although further studies to improve their delivery method are needed to elucidate its potential in ISR.


Assuntos
Canal de Potássio Kv1.3/antagonistas & inibidores , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Bloqueadores dos Canais de Potássio/farmacologia , Túnica Íntima/patologia , Aloenxertos/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Reestenose Coronária/patologia , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/lesões , Vasos Coronários/patologia , Modelos Animais de Doenças , Feminino , Artéria Femoral/efeitos dos fármacos , Artéria Femoral/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperplasia , Canal de Potássio Kv1.3/genética , Canal de Potássio Kv1.3/metabolismo , Canal de Potássio Kv1.5/genética , Canal de Potássio Kv1.5/metabolismo , Modelos Biológicos , Miócitos de Músculo Liso/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Stents , Suínos , Túnica Íntima/efeitos dos fármacos
2.
PLoS One ; 15(5): e0232483, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32392256

RESUMO

BACKGROUND: Percutaneous coronary intervention represents the most important treatment modality of coronary artery stenosis. In-stent restenosis (ISR) is still a limitation for the long-term outcome despite the introduction of drug eluting stents. It has been shown that adipokines directly influence vessel wall homeostasis by influencing the function of endothelial cells and arterial smooth muscle cells. Visceral adipose tissue-derived serpin vaspin was recently identified as a member of serine protease inhibitor family and serveral studies could demonstrate a relation to metabolic diseases. The aim of this study was to investigate a role of vaspin in the development of in-stent restenosis in vivo and on migration of smooth muscle cells and endothelial cells in vitro. METHODS: We studied 85 patients with stable coronary artery disease who underwent elective and successful PCI with implatation of drug eluting stents. Blood samples were taken directly before PCI. Vaspin plasma levels were measured by specific ELISA. ISR was evaluated eight months later by coronary angiography. Human coronary artery smooth muscle cells (HCASMC) and human umbilical vein endothelial cells (HUVEC) migration was analyzed by an in-vitro migration assay with different concentrations (0.004ng/mL up to 40ng/mL) of vaspin as well as by an scratch assay. For proliferation an impedance measurement with specialiced E-Plates was performed. RESULTS: During the follow up period, 14 patients developed ISR. Patients with ISR had significantly lower vaspin plasma levels compared to patients without ISR (0.213 ng/ml vs 0.382 ng/ml; p = 0.001). In patients with plasma vaspin levels above 1.35 ng/ml we could not observe any restenosis. There was also a significant correlation of plasma vaspin levels and late lumen loss in the stented coronary segments. Further we could demonstrate that vaspin nearly abolishes serum induced migration of HCASMC (100% vs. 9%; p<0.001) in a biphasic manner but not migration of HUVEC. Proliferation of HCASMC and HUVEC was not modulated by vaspin treatment. CONCLUSION: We were able to show that the adipokine vaspin selectively inhibits human coronary SMC migration in vitro and has no effect on HUVEC migration. Vaspin had no effect on proliferation of HUVEC which is an important process of the healing of the stented vessel. In addition, the occurrence of ISR after PCI with implantation of drug eluting stents was significantly associated with low vaspin plasma levels before intervention. Determination of vaspin plasma levels before PCI might be helpful in the identification of patients with high risk for development of ISR after stent implantation. In addition, the selective effects of vaspin on smooth muscle cell migration could potentially be used to reduce ISR without inhibition of re-endothelialization of the stented segment.


Assuntos
Adipocinas/fisiologia , Reestenose Coronária/etiologia , Intervenção Coronária Percutânea/efeitos adversos , Serpinas/fisiologia , Adipocinas/sangue , Adipocinas/farmacologia , Idoso , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células Cultivadas , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/cirurgia , Reestenose Coronária/patologia , Reestenose Coronária/fisiopatologia , Vasos Coronários/patologia , Vasos Coronários/fisiopatologia , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/fisiologia , Serpinas/sangue , Serpinas/farmacologia
3.
Cardiovasc Pathol ; 45: 107177, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31891881

RESUMO

BACKGROUND: Coronary artery stenting has become a common procedure and cardiovascular pathology specimens containing these metallic stents are accordingly becoming common. Histologic examination of stented vessels is imperative, but special techniques are needed due to the presence of metal within the tissue. We describe a rapid and inexpensive method for preparing stented vascular specimens for routine histology suitable for use in almost any histology laboratory. DESIGN: After formalin fixation and decalcification, stented vascular segments were freeze-embedded and sectioned using a handheld power micro cutoff wheel tool into ~1 mm slices. Sections were allowed to thaw and the strut shards removed with fine forceps. No longer containing metal, the sections were processed for routine paraffin embedding, microtomy and staining. RESULTS: Histologic sections showed only minor tissue disruption around the stent struts. In our experience with 25 stented arteries (mean interval from implantation 5.6 years), the mean subjective section quality score was 4.1 out of 5. The position of each strut could easily be determined, along with neointimal in-stent restenosis and thrombosis. Local reaction to each strut could be surmised even if minor tissue disruption occurred. The entire process was completed in 2-3 days. The incremental cost over that of routine histology is nominal. CONCLUSION: This method for examining stented vascular segments histologically could readily be applied in most pathology laboratories and serves as a highly practical solution to dilemma of examining stents histologically.


Assuntos
Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/terapia , Reestenose Coronária/patologia , Vasos Coronários/patologia , Metais , Intervenção Coronária Percutânea/instrumentação , Manejo de Espécimes , Stents , Trombose/patologia , Reestenose Coronária/etiologia , Técnica de Descalcificação , Humanos , Microtomia , Inclusão em Parafina , Intervenção Coronária Percutânea/efeitos adversos , Desenho de Prótese , Coloração e Rotulagem , Trombose/etiologia , Fatores de Tempo , Fixação de Tecidos , Fluxo de Trabalho
4.
In Vivo ; 34(1): 433-439, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31882510

RESUMO

BACKGROUND/AIM: Restenosis and stent fractures are well-characterised treatment failures following femoropopliteal (FP) stent-based interventions. We aimed to determine patterns of restenosis and fracture rates following focal stenting of FP arteries. PATIENTS AND METHODS: This retrospective study investigated angiographic patterns of restenosis and the occurrence of stent fractures following focal FP stenting with the multiple stent delivery system VascuFlex® Multi-LOC. RESULTS: We identified 10 patients with 10 (of 129) FP lesions (mean length 11.7±4.6 cm) and a total of 51 (of 646) Multi-LOC stents that underwent clinically driven target lesion revascularizations (TLR) after 11.5±9.2 months, due to symptomatic recurrence of stenosis. None of the Multi-LOC stents had fractured. No isolated in-stent restenosis (>50%) was observed. Median diameter lumen loss was significantly more pronounced at the inter-stent segments (27.0%) compared to in-stent segments (7.8%, p=0.023). CONCLUSION: No evidence of fracture or susceptibility to stent-related restenosis using Multi-LOC stents was observed. Focal FP stenting may be more effective when combined with strategies known to reduce restenosis in non-stented artery segments.


Assuntos
Constrição Patológica/terapia , Reestenose Coronária/terapia , Artéria Femoral/fisiopatologia , Artéria Poplítea/fisiopatologia , Stents/efeitos adversos , Procedimentos Cirúrgicos Vasculares/instrumentação , Idoso , Constrição Patológica/patologia , Reestenose Coronária/etiologia , Reestenose Coronária/patologia , Feminino , Artéria Femoral/cirurgia , Seguimentos , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Procedimentos Cirúrgicos Vasculares/métodos
5.
Cardiovasc Res ; 116(3): 505-519, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31397850

RESUMO

Coronary artery disease (CAD) remains one of the most important causes of morbidity and mortality worldwide, and the availability of percutaneous or surgical revascularization procedures significantly improves survival. However, both strategies are daunted by complications which limit long-term effectiveness. In-stent restenosis (ISR) is a major drawback for intracoronary stenting, while graft failure is the limiting factor for coronary artery bypass graft surgery (CABG), especially using veins. Conversely, internal thoracic artery (ITA) is known to maintain long-term patency in CABG. Understanding the biology and pathophysiology of ISR and vein graft failure (VGF) and mechanisms behind ITA resistance to failure is crucial to combat these complications in CAD treatment. This review intends to provide an overview of the biological mechanisms underlying stent and VGF and of the potential therapeutic strategy to prevent these complications. Interestingly, despite being different modalities of revascularization, mechanisms of failure of stent and saphenous vein grafts are very similar from the biological standpoint.


Assuntos
Ponte de Artéria Coronária/efeitos adversos , Doença da Artéria Coronariana/terapia , Reestenose Coronária/prevenção & controle , Vasos Coronários/cirurgia , Oclusão de Enxerto Vascular/prevenção & controle , Artéria Torácica Interna/cirurgia , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/instrumentação , Veia Safena/transplante , Stents , Animais , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/fisiopatologia , Reestenose Coronária/metabolismo , Reestenose Coronária/patologia , Reestenose Coronária/fisiopatologia , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Vasos Coronários/fisiopatologia , Oclusão de Enxerto Vascular/metabolismo , Oclusão de Enxerto Vascular/patologia , Oclusão de Enxerto Vascular/fisiopatologia , Humanos , Artéria Torácica Interna/metabolismo , Artéria Torácica Interna/fisiopatologia , Neointima , Fatores de Risco , Veia Safena/metabolismo , Veia Safena/fisiopatologia , Fatores de Tempo , Falha de Tratamento , Grau de Desobstrução Vascular
7.
BMJ Case Rep ; 12(10)2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666250

RESUMO

An 81-year-old, functionally independent woman with a history of bypass surgery and a previous vein graft intervention presented to us with significant angina refractory to medical management. An urgent angiogram revealed severe in-stent restenosis (ISR) in the proximal stent of the right coronary artery graft. At the same time, multiple trials to predilate the tight ISR using various-sized non-compliant and cutting balloons were unsuccessful. During the second attempt the next day, rotational atherectomy was used for plaque modification as the lesion appeared fibrocalcific angiographically. A good imaging result was obtained after final dilatation with a drug-eluting balloon, and the patient also achieved immediate angina relief. Even though rotational atherectomy is contraindicated in vein graft interventions, it can be successfully used in selected cases when routine angioplasty techniques fail.


Assuntos
Angina Pectoris/etiologia , Aterectomia Coronária/métodos , Reestenose Coronária/diagnóstico por imagem , Oclusão de Enxerto Vascular/diagnóstico por imagem , Idoso de 80 Anos ou mais , Angiografia/métodos , Angioplastia Coronária com Balão/métodos , Reestenose Coronária/patologia , Stents Farmacológicos , Feminino , Humanos , Placa Aterosclerótica/terapia , Stents/efeitos adversos , Resultado do Tratamento
8.
Cardiovasc Eng Technol ; 10(4): 568-582, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31531821

RESUMO

BACKGROUND: Coronary artery restenosis is an important side effect of percutaneous coronary intervention. Computational models can be used to better understand this process. We report on an approach for validation of an in silico 3D model of in-stent restenosis in porcine coronary arteries and illustrate this approach by comparing the modelling results to in vivo data for 14 and 28 days post-stenting. METHODS: This multiscale model includes single-scale models for stent deployment, blood flow and tissue growth in the stented vessel, including smooth muscle cell (SMC) proliferation and extracellular matrix (ECM) production. The validation procedure uses data from porcine in vivo experiments, by simulating stent deployment using stent geometry obtained from micro computed tomography (micro-CT) of the stented vessel and directly comparing the simulation results of neointimal growth to histological sections taken at the same locations. RESULTS: Metrics for comparison are per-strut neointimal thickness and per-section neointimal area. The neointimal area predicted by the model demonstrates a good agreement with the detailed experimental data. For 14 days post-stenting the relative neointimal area, averaged over all vessel sections considered, was 20 ± 3% in vivo and 22 ± 4% in silico. For 28 days, the area was 42 ± 3% in vivo and 41 ± 3% in silico. CONCLUSIONS: The approach presented here provides a very detailed, location-specific, validation methodology for in silico restenosis models. The model was able to closely match both histology datasets with a single set of parameters. Good agreement was obtained for both the overall amount of neointima produced and the local distribution. It should be noted that including vessel curvature and ECM production in the model was paramount to obtain a good agreement with the experimental data.


Assuntos
Angioplastia Coronária com Balão/instrumentação , Simulação por Computador , Reestenose Coronária/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Imageamento Tridimensional , Modelos Cardiovasculares , Stents , Microtomografia por Raio-X , Angioplastia Coronária com Balão/efeitos adversos , Animais , Reestenose Coronária/etiologia , Reestenose Coronária/patologia , Vasos Coronários/patologia , Modelos Animais de Doenças , Matriz Extracelular/patologia , Miócitos de Músculo Liso/patologia , Neointima , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Sus scrofa , Fatores de Tempo
9.
EBioMedicine ; 46: 274-289, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31395500

RESUMO

BACKGROUND: Tumor necrosis factor-like weak inducer of apoptosis (Tnfsf12; TWEAK) and its receptor Fibroblast growth factor-inducible 14 (Tnfrsf12a; Fn14) participate in the inflammatory response associated with vascular remodeling. However, the functional effect of TWEAK on vascular smooth muscle cells (VSMCs) is not completely elucidated. METHODS: Next generation sequencing-based methods were performed to identify genes and pathways regulated by TWEAK in VSMCs. Flow-citometry, wound-healing scratch experiments and transwell migration assays were used to analyze VSMCs proliferation and migration. Mouse wire injury model was done to evaluate the role of TWEAK/Fn14 during neointimal hyperplasia. FINDINGS: TWEAK up-regulated 1611 and down-regulated 1091 genes in VSMCs. Using a gene-set enrichment method, we found a functional module involved in cell proliferation defined as the minimal network connecting top TWEAK up-regulated genes. In vitro experiments in wild-type or Tnfrsf12a deficient VSMCs demonstrated that TWEAK increased cell proliferation, VSMCs motility and migration. Mechanistically, TWEAK increased cyclins (cyclinD1), cyclin-dependent kinases (CDK4, CDK6) and decreased cyclin-dependent kinase inhibitors (p15lNK4B) mRNA and protein expression. Downregulation of p15INK4B induced by TWEAK was mediated by mitogen-activated protein kinase ERK and Akt activation. Tnfrsf12a or Tnfsf12 genetic depletion and pharmacological intervention with TWEAK blocking antibody reduced neointimal formation, decreasing cell proliferation, cyclin D1 and CDK4/6 expression, and increasing p15INK4B expression compared with wild type or IgG-treated mice in wire-injured femoral arteries. Finally, immunohistochemistry in human coronary arteries with stenosis or in-stent restenosis revealed high levels of Fn14, TWEAK and PCNA in VSMCs enriched areas of the neointima as compared with healthy coronary arteries. INTERPRETATION: Our data define a major role of TWEAK/Fn14 in the control of VSMCs proliferation and migration during neointimal hyperplasia after wire injury in mice, and identify TWEAK/Fn14 as a potential target for treating in-stent restenosis. FUND: ISCiii-FEDER, CIBERCV and CIBERDEM.


Assuntos
Angioplastia/efeitos adversos , Reestenose Coronária/etiologia , Reestenose Coronária/metabolismo , Citocina TWEAK/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor de TWEAK/metabolismo , Animais , Biomarcadores , Movimento Celular , Proliferação de Células , Reestenose Coronária/patologia , Modelos Animais de Doenças , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Modelos Biológicos , Miócitos de Músculo Liso/metabolismo , Complicações Pós-Operatórias , Túnica Íntima/metabolismo , Túnica Íntima/patologia
11.
Int J Cardiovasc Imaging ; 35(10): 1755-1763, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31127455

RESUMO

To investigate the correlations between the three-dimensional (3D) parameters of target coronary artery segments and restenosis after stent implantation. Sixty-four patients after single, cobalt chromium platform stent (27 BM stents and 37 DES) implantation were investigated retrospectively 12 ± 6 months after the index procedure. 3D coronary artery reconstruction was performed before and after the stent implantation using appropriate projections by a dedicated reconstruction software. The curve of the target segment was characterized by the ratio of the vessel length measured at midline (arc: A) and the distance between the edge points of the stent (chord: C): A/C ratio (ACr). Age, diabetes and hyperlipidaemia were taken into account for the statistical evaluation. 22 patients were diagnosed with ISR, while 42 patients without any restenosis served as controls. The two groups did not differ regarding major cardiovascular risk factors, proportion of the treated vessels or the type of stents. Higher initial ACr values were associated with greater straightening of the vessel curvature in all groups (p < 0.001). Significant negative correlations were found in cases of proximal or distal edge bending angles (p < 0.001). Pre-stent edge bending angles < 7° often showed an increase after the stent implantation, while in case of higher initial values, the bending angles generally decreased. Using multivariate logistic regression modelling we found that the pre-stent ACr was an independent predictor of in-stent restenosis (odds ratio for 1% increase of the ACr: 1.08; p = 0.012). Changes of angles at the stent edges following stent implantation correlate with the initial local bending angles. The ACr predispose to chronic shear stress in the vessel wall, which may contribute to the pathological intimal proliferation.


Assuntos
Angiografia por Tomografia Computadorizada/métodos , Angiografia Coronária/métodos , Doença da Artéria Coronariana/terapia , Reestenose Coronária/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Imageamento Tridimensional , Intervenção Coronária Percutânea/instrumentação , Stents , Idoso , Proliferação de Células , Ligas de Cromo , Doença da Artéria Coronariana/diagnóstico por imagem , Reestenose Coronária/etiologia , Reestenose Coronária/patologia , Vasos Coronários/patologia , Stents Farmacológicos , Feminino , Humanos , Hungria , Masculino , Pessoa de Meia-Idade , Neointima , Intervenção Coronária Percutânea/efeitos adversos , Valor Preditivo dos Testes , Interpretação de Imagem Radiográfica Assistida por Computador , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
12.
Eur J Pharmacol ; 855: 167-174, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31075238

RESUMO

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.


Assuntos
Antioxidantes/farmacologia , Artérias Carótidas/efeitos dos fármacos , Reestenose Coronária/tratamento farmacológico , Flavanonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antioxidantes/uso terapêutico , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Reestenose Coronária/metabolismo , Reestenose Coronária/patologia , Flavanonas/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Hiperplasia/patologia , Inflamação/metabolismo , Interleucina-1beta/sangue , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Receptores de Superfície Celular/metabolismo , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/sangue
13.
Eur Heart J ; 40(31): 2607-2615, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31079155

RESUMO

AIMS: Randomized clinical trials have consistently demonstrated the non-inferiority of bioabsorbable polymer drug-eluting stents (BP-DES) with respect to DES having permanent polymers (PP-DES). To date, the comparative performance of BP- and PP-DES in the real world has not been extensively investigated. METHODS AND RESULTS: From October 2011 to June 2016, we analysed the outcomes associated with newer generation DES use in Sweden. After stratification according to the type of DES received at the index procedure, a total of 16 504 and 79 106 stents were included in the BP- and PP-DES groups, respectively. The Kaplan-Meier estimates for restenosis at 2 years were 1.2% and 1.4% in BP- and PP-DES groups, respectively. Definite stent thrombosis (ST) was low in both groups (0.5% and 0.7% in BP- and PP-DES groups, respectively). The adjusted hazard ratio (HR) for either restenosis or definite ST did not differ between BP- and PP-DES [adjusted HR 0.95, 95% confidence interval (CI) 0.74-1.21; P = 0.670 and adjusted HR 0.79, 95% CI 0.57-1.09; P = 0.151, respectively]. Similarly, there were no differences in the adjusted risk of all-cause death and myocardial infarction (MI) between the two groups (adjusted HR for all-cause death 1.01, 95% CI 0.82-1.25; P = 0.918 and adjusted HR for MI 1.05, 95% CI 0.93-1.19; P = 0.404). CONCLUSION: In a large, nationwide, and unselected cohort of patients, percutaneous coronary intervention with BP-DES implantation was not associated with an incremental clinical benefit over PP-DES use at 2 years follow-up.


Assuntos
Implantes Absorvíveis/efeitos adversos , Síndrome Coronariana Aguda/terapia , Angiografia Coronária/estatística & dados numéricos , Doença da Artéria Coronariana/terapia , Stents Farmacológicos/efeitos adversos , Implantes Absorvíveis/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Angioplastia Coronária com Balão/métodos , Causas de Morte/tendências , Angiografia Coronária/métodos , Reestenose Coronária/epidemiologia , Reestenose Coronária/patologia , Stents Farmacológicos/estatística & dados numéricos , Humanos , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/mortalidade , Ensaios Clínicos Controlados não Aleatórios como Assunto , Intervenção Coronária Percutânea/métodos , Polímeros , Estudos Prospectivos , Desenho de Prótese , Falha de Prótese/tendências , Sistema de Registros , Suécia/epidemiologia
15.
Int J Mol Med ; 43(3): 1299-1310, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30747216

RESUMO

Restenosis is liable to occur following treatment with endovascular interventional therapy. Increasing evidence indicates that hydrogen sulfide (H2S) exhibits numerous physiological properties, including antioxidative and cardioprotective disease properties. Thus, the present study aimed to investigate the anti­restenosis effects of H2S and its protective mechanisms. A balloon dilatation restenosis model was used, in which model Sprague­Dawley rats were treated with sodium hydrosulfide (NaHS: A donor of H2S, 30 µmol/kg) by intraperitoneal injection for 4 weeks. Histological observations of the carotid artery were performed, and H2S production and the expression of Nuclear factor­E2­related factor 2 (Nrf2)/hypoxia­inducible factor (HIF)­1α signaling pathway proteins were measured. In addition, human umbilical vein endothelial cells (HUVECs) were treated with NaHS following the inhibition of Nrf2 or HIF­1α expression. The expression of Nrf2/HIF­1α signaling pathway proteins, tube formation and cell migration were evaluated thereafter. The results demonstrated that NaHS treatment significantly increased H2S production in rats with restenosis, and that neointimal thickness decreased significantly in arteries with restenosis. Furthermore, an increase in H2S production enhanced the nuclear accumulation of Nrf2 and expression of its downstream targets, heme oxygenase­1 and superoxide dismutase, as well as HIF­1α. Similar effects of NaHS on the expression of these proteins were observed in HUVECs. Additionally, these findings indicated that NaHS­induced HIF­1α expression was dependent on Nrf2 expression. NaHS treatment also markedly increased tube formation by upregulating vascular endothelial growth factor expression and cell migration, both of which were mediated by the Nrf2/HIF­1α signaling pathway, and suppressed the migration and proliferation of human vascular smooth muscle cells. Thus, NaHS­mediated H2S production was observed to prevent neointimal hyperplasia, promote activation of the Nrf2/HIF­1α signal pathway, and enhance HUVEC tube formation and migration, thereby exerting protective effects on balloon injury­induced restenosis.


Assuntos
Cardiotônicos/farmacologia , Reestenose Coronária/patologia , Sulfeto de Hidrogênio/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais , Animais , Antioxidantes/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hiperplasia , Masculino , Miócitos de Músculo Liso/metabolismo , Neointima/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Substâncias Protetoras , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sulfetos/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
16.
Clin Investig Arterioscler ; 31(2): 49-55, 2019.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30773346

RESUMO

OBJECTIVE: To determine the relation between epicardial fat thickness and coronary in-stent restenosis in patients with acute myocardial infarction and percutaneous coronary intervention. METHODS: A prospective study was conducted, which included 129 patients (67.3% male, mean age 62.9±10 years) with ST segment elevation acute myocardial infarction undergoing primary percutaneous coronary intervention with bare metal stent. Patients were divided in two groups according to the presence (n=21) or not (n=108) of in-stent restenosis during one year follow-up. RESULTS: Epicardial fat was significantly thicker in patients with coronary in-stent restenosis (5.51±1.6 vs 4.14±2.0mm, p=0.006). A proportionally and significantly thicker epicardial fat was found according to the increase in coronary disease severity (3.3±0.9mm vs 4.3±1.8mm vs 4.7±2.3mm vs 6.7±2.2mm, for type A, B1, B2 and C lesions, respectively, p=0.001) and number of vessels (3.07±1.2mm vs 4.92±1.8mm vs 5.43±2.2mm, for one, two and three vessels disease, respectively, p<0.0001). Epicardial fat thickness ≥4.7mm had 75.0% sensibility and 69.0% specificity for predicting restenosis (AUC=0.737). CONCLUSIONS: Echocardiographic evaluation of epicardial fat thickness could identify those patients with acute myocardial infarction with greater probabilities of in-stent restenosis after percutaneous coronary intervention.


Assuntos
Reestenose Coronária/epidemiologia , Intervenção Coronária Percutânea/métodos , Pericárdio/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Stents , Tecido Adiposo/diagnóstico por imagem , Idoso , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/terapia , Reestenose Coronária/patologia , Ecocardiografia/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade , Resultado do Tratamento
17.
IUBMB Life ; 71(5): 632-642, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30597731

RESUMO

Vascular smooth muscle cell (VSMC) hyperproliferation is the main pathological process in various cardiovascular diseases, such as vascular restenosis. This process may be repressed by RING finger protein 10 (RNF10) in metabolic syndrome (MetS) rats. The aim of this study is to evaluate the inhibitory effects and molecular mechanisms of RNF10 on VSMC hyperproliferation. Neointimal hyperplasia in MetS and high-glucose-induced VSMC hyperproliferation were measured after infection with adenoviruses encoding RNF10 (Ad-RNF10), short hairpin RNF10 (Ad-shRNF10), or green fluorescent protein (Ad-GFP). In vivo and in vitro, we found that overexpression of RNF10 significantly affected neointima formation and VSMC proliferation, and displayed further inhibitory activity by promoting mesenchyme homeobox 2 (Meox2) and suppressing activating protein 1 (AP-1). In contrast, Ad-shRNF10 had an opposite effect on neointimal hyperplasia and VSMC hyperproliferation in vivo and in vitro. Our study indicated that RNF10 inhibited the hyperproliferation with the activities of Meox2 and AP-1 proteins. RNF10 may be a next drug target for treating vascular restenosis and other related cardiovascular diseases. © 2018 IUBMB Life, 71(5):632-642, 2019.


Assuntos
Proteínas de Transporte/metabolismo , Proliferação de Células , Reestenose Coronária/prevenção & controle , Hiperplasia/prevenção & controle , Síndrome Metabólica/fisiopatologia , Músculo Liso Vascular/citologia , Neointima , Proteínas do Tecido Nervoso/metabolismo , Adenoviridae/fisiologia , Infecções por Adenoviridae/virologia , Angioplastia Coronária com Balão/efeitos adversos , Animais , Proteínas de Transporte/genética , Movimento Celular , Células Cultivadas , Reestenose Coronária/etiologia , Reestenose Coronária/patologia , Dieta Hiperlipídica/efeitos adversos , Hiperplasia/etiologia , Hiperplasia/patologia , Masculino , Síndrome Metabólica/etiologia , Músculo Liso Vascular/metabolismo , Proteínas do Tecido Nervoso/genética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
18.
Angiology ; 70(3): 272-278, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29338303

RESUMO

This retrospective, single-center study assessed the prognostic value of several emerging inflammatory markers as predictors of in-stent restenosis (ISR) after drug-eluting stent implantation for coronary chronic total occlusion (CTO) lesions. Consecutive patients (n = 416) who underwent successful percutaneous coronary intervention (PCI) for documented CTO lesions and with follow-up angiography were enrolled. Preprocedural high-sensitivity C-reactive protein (hsCRP), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and red cell distribution width (RDW) were analyzed. At mean follow-up of 14.4 ± 3.3 months, ISR occurred in 72 patients. Compared with the non-ISR group, preprocedural hsCRP level, PLR, NLR, and RDW were significantly higher in the ISR group. The ISR group also had significantly greater proportions of patients with diabetes and smoking history, lower estimated glomerular filtration rate, higher low-density lipoprotein cholesterol (LDL-C) level and neutrophil count, longer stent length, and higher rate of severe dissection. In multivariate analysis, NLR (odds ratio [OR]: 3.110; 95% confidence interval [CI], 2.102-4.063; P < .001) and PLR (OR: 1.029; 95% CI, 1.016-1.143; P < .001) were independent predictors of ISR, along with LDL-C level and stent length. In conclusion, higher preprocedural NLR and PLR levels were independent risk factors for the development of ISR in patients who underwent PCI for CTO lesions.


Assuntos
Reestenose Coronária/patologia , Stents Farmacológicos , Linfócitos/patologia , Angiografia Coronária/efeitos adversos , Reestenose Coronária/diagnóstico , Reestenose Coronária/etiologia , Stents Farmacológicos/efeitos adversos , Feminino , Humanos , Masculino , Neutrófilos/patologia , Intervenção Coronária Percutânea/métodos , Fatores de Risco
20.
Singapore Med J ; 60(1): 48-51, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29632955

RESUMO

INTRODUCTION: The pathophysiology and mechanism of in-stent restenosis (ISR) after implantation of second-generation drug-eluting stents (DESs) are not fully clear. We compared the morphological characteristics of ISR between first- and second-generation DESs using frequency domain optical coherence tomography (OCT). METHODS: Patients who underwent follow-up coronary angiography (CAG) after first-generation (CYPHER™ and TAXUS™) and second-generation (Nobori®, PROMUS Element™, Resolute Integrity and XIENCE) DES implantations were examined. ISR was defined as lesions of over 50% diameter stenosis at follow-up CAG. Frequency domain OCT was performed at the time of revascularisation of ISR. Tissue morphology was assessed at minimum lumen area. OCT images of DESs at both early (≤ 1 year) and late (> 1 year) phase follow-up were compared. RESULTS: On qualitative OCT assessment, the ratios of homogeneous, layered, heterogeneous without-attenuation and heterogeneous with-attenuation morphologies were 57.1%, 17.1%, 20.0% and 5.7%, respectively, for second-generation DES ISR (n = 35), and 16.7%, 25.0%, 25.0% and 33.3%, respectively, for first-generation DES ISR (n = 36). At late phase follow-up, homogeneous morphology was significantly more common for second-generation DES ISR compared to first-generation DES ISR (first-generation: 8.0% vs. second-generation: 50.0%; p < 0.01) while heterogeneous with-attenuation morphology was significantly more common for first-generation DES ISR (first-generation: 44.0% vs. second-generation: 5.6%; p < 0.01). CONCLUSION: Homogeneous tissue morphology was more frequently found for second-generation than first-generation DES ISR, especially in the late phase. This suggested that neointimal hyperplasia was the main mechanism in second-generation DES ISR, and that the neointima was stabilised, much like in bare metal stent implantation.


Assuntos
Reestenose Coronária/diagnóstico por imagem , Vasos Coronários/cirurgia , Stents Farmacológicos/efeitos adversos , Tomografia de Coerência Óptica , Idoso , Constrição Patológica/patologia , Angiografia Coronária , Reestenose Coronária/patologia , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/patologia , Feminino , Humanos , Incidência , Masculino , Metais , Pessoa de Meia-Idade , Neointima , Estudos Retrospectivos
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