RESUMEN
BACKGROUND: Iliofemoral deep vein thrombosis (IFDVT) causes severe symptoms and affect the quality of life to a great extent. Endovascular thrombectomy and stent implantation have been a feasible strategie to alleviate the signs and symptoms of IFDVT. However, venous in-stent restenosis (ISR) has become an emerging non-negligible problem. METHODS: To evaluate the histological characteristics of venous ISR, neointima of arterial and venous ISR patients were collected and examed. To explore the effect of drug-coated balloon (DCB) on venous ISR lesions, we conducted a single-center retrospective case series study involving IFDVT patients with ISR after venous stenting who were treated with paclitaxel-coated balloon dilatation. RESULTS: We found a collagen-rich matrix but not elastin, as well as fewer cells and less neovascularization in venous intimal hyperplasia compared with neointima in arteries. Thirteen IFDVT patients were involved in the study, with average preoperative stenosis degree of 87.69% ± 13.48%. After intervention, the stenosis degree was significantly reduced to 14.6% ± 14.36% immediately (p < 0.0001) and to 16.54% ± 15.73% during follow-up (p < 0.0001). During follow-up, the VEINES-QOL scores (p < 0.0001), VEINES-Sym scores (p < 0.0001), and Villalta scores (p = 0.04) of patients was improved significantly compared with those before intervention. No major adverse events were observed. CONCLUSIONS: The use of DCB may have a positive effect in the treatment of venous ISR by targeting intimal hyperplasia. Moreover, the application of DCB dilatation in IFDVT stenting patients with ISR is deemed safe and effective.
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Angioplastia Coronaria con Balón , Reestenosis Coronaria , Trombosis de la Vena , Humanos , Angioplastia Coronaria con Balón/efectos adversos , Calidad de Vida , Constricción Patológica/inducido químicamente , Reestenosis Coronaria/etiología , Estudios Retrospectivos , Neointima/inducido químicamente , Neointima/complicaciones , Hiperplasia/inducido químicamente , Hiperplasia/complicaciones , Resultado del Tratamiento , Stents/efectos adversos , Paclitaxel/efectos adversos , Trombosis de la Vena/diagnóstico por imagen , Trombosis de la Vena/terapia , Materiales Biocompatibles RevestidosRESUMEN
INTRODUCTION: Arterial restenosis caused by intimal hyperplasia (IH) is a serious complication after vascular interventions. In the rat carotid balloon injury model, we injected phosphate buffer saline (PBS), rapamycin-phosphate buffer saline suspension (RPM-PBS), blank fibrin glue (FG) and rapamycin-fibrin glue (RPM-FG) around the injured carotid artery under ultrasound guidance and observed the inhibitory effect on IH. METHODS: The properties of RPM-FG in vitro were verified by scanning electron microscopy (SEM) and determination of the drug release rate. FG metabolism in vivo was observed by fluorescence imaging. The rat carotid balloon injury models were randomly classified into 4 groups: PBS group (control group), RPM-PBS group, FG group, and RPM-FG group. Periadventitial administration was performed by ultrasound-guided percutaneous puncture on the first day after angioplasty. Carotid artery specimens were analyzed by immunostaining, Evans blue staining and hematoxylin-eosin staining. RESULTS: The RPM particles showed clustered distributions in the FG block. The glue was maintained for a longer time in vivo (> 14 days) than in vitro (approximately 7 days). Two-component liquid FG administered by ultrasound-guided injection completely encapsulated the injured artery before coagulation. The RPM-FG inhibited IH after carotid angioplasty vs. control and other groups. The proliferation of vascular smooth muscle cells (VSMCs) was significantly inhibited during neointima formation, whereas endothelial cell (EC) repair was not affected. CONCLUSION: Periadventitial delivery of RPM-FG contributed to inhibiting IH in the rat carotid artery injury model without compromising re-endothelialization. Additionally, FG provided a promising platform for the future development of a safe, effective, and minimally invasive perivascular drug delivery method to treat vascular disease.
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Traumatismos de las Arterias Carótidas , Neointima , Ratas , Animales , Hiperplasia/tratamiento farmacológico , Hiperplasia/complicaciones , Neointima/tratamiento farmacológico , Neointima/complicaciones , Adhesivo de Tejido de Fibrina/farmacología , Adhesivo de Tejido de Fibrina/uso terapéutico , Proliferación Celular , Ratas Sprague-Dawley , Traumatismos de las Arterias Carótidas/tratamiento farmacológico , Traumatismos de las Arterias Carótidas/metabolismo , Ultrasonografía Intervencional , FosfatosRESUMEN
OBJECTIVE: Neointimal hyperplasia is the primary mechanism underlying atherosclerosis and restenosis after percutaneous coronary intervention. Ketogenic diet (KD) exerts beneficial effects in various diseases, but whether it could serve as non-drug therapy for neointimal hyperplasia remains unknown. This study aimed to investigate the effect of KD on neointimal hyperplasia and the potential mechanisms. METHODS AND RESULTS: Carotid artery balloon-injury model was employed in adult Sprague-Dawley rats to induce neointimal hyperplasia. Then, animals were subjected to either standard rodent chow or KD. For in-vitro experiment, impacts of ß-hydroxybutyrate (ß-HB), the main mediator of KD effects, on platelet-derived growth factor BB (PDGF-BB) induced vascular smooth muscle cell (VSMC) migration and proliferation were determined. Balloon injury induced event intimal hyperplasia and upregulation of protein expression of proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (α-SMA), and these changes were significantly ameliorated by KD. In addition, ß-HB could markedly inhibit PDGF-BB induced VMSC migration and proliferation, as well as inhibiting expressions of PCNA and α-SMC. Furthermore, KD inhibited balloon-injury induced oxidative stress in carotid artery, indicated by reduced ROS level, malondialdehyde (MDA) and myeloperoxidase (MPO) activities, and increased superoxide dismutase (SOD) activity. We also found balloon-injury induced inflammation in carotid artery was suppressed by KD, indicated by decreased expressions of proinflammatory cytokines IL-1ß and TNF-α, and increased expression of anti-inflammatory cytokine IL-10. CONCLUSION: KD attenuates neointimal hyperplasia through suppressing oxidative stress and inflammation to inhibit VSMC proliferation and migration. KD may represent a promising non-drug therapy for neointimal hyperplasia associated diseases.
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Traumatismos de las Arterias Carótidas , Dieta Cetogénica , Ratas , Animales , Hiperplasia/complicaciones , Ratas Sprague-Dawley , Becaplermina/metabolismo , Becaplermina/farmacología , Becaplermina/uso terapéutico , Antígeno Nuclear de Célula en Proliferación/metabolismo , Antígeno Nuclear de Célula en Proliferación/farmacología , Antígeno Nuclear de Célula en Proliferación/uso terapéutico , Neointima/complicaciones , Neointima/tratamiento farmacológico , Neointima/metabolismo , Traumatismos de las Arterias Carótidas/complicaciones , Traumatismos de las Arterias Carótidas/tratamiento farmacológico , Traumatismos de las Arterias Carótidas/metabolismo , Estrés Oxidativo , Inflamación/complicaciones , Proliferación Celular , Movimiento Celular , Células CultivadasRESUMEN
Wedge thrombus formation around the inflow cannula of a continuous left ventricular assist device (LVAD) is a source of systemic thromboemboli. We previously reported the potential advantages of a new inflow cannula wrapped with titanium mesh (GU30) over the standard smooth surface oblique cut cannula (GU10). The objective of the present study was to clinically validate this new cannula. A retrospective cohort analysis of patients with implanted LVAD (EVAHEART) comparing the GU10 to the GU30 was conducted. Clinical outcomes, including survival, the incidence of thromboembolism, and bleeding events, were compared. Gross and histopathological analyses of explanted GU30 cannula were conducted following transplant or patient death. No significant differences in the survival rate, severe emboli, or cerebral bleeding were observed during the LVAD implantation. However, severe emboli occurred earlier after LVAD implantation when using the GU30 cannula compared with the GU10. In cases of long LVAD support, the neointima fully covered the inflow of the GU30 cannulae without wedge thrombus formation. The titanium mesh-wrapped inflow cannulae did not reduce the overall incidence of neurological events significantly. However, the titanium mesh-wrapped inflow cannula induced autologous neointimal growth over the cannula and prevented wedge thrombus formation in late-phase LVAD implantation.
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Corazón Auxiliar , Tromboembolia , Trombosis , Humanos , Cánula/efectos adversos , Estudios Retrospectivos , Corazón Auxiliar/efectos adversos , Neointima/complicaciones , Titanio , Trombosis/etiología , Trombosis/prevención & controlRESUMEN
Restenosis is a severe complication after percutaneous transluminal coronary angioplasty which limits the long-term efficacy of the intervention. In this study, we investigated the efficiency of exosomes derived from AT2R-overexpressing bone mesenchymal stem cells on the prevention of restenosis after carotid artery injury. Our data showed that AT2R-EXO promoted the proliferation and migration of vascular endothelial cells and maintained the ratio of eNOS/iNOS. On the contrary, AT2R-EXO inhibited the proliferation and migration of vascular smooth muscle cells. In vivo study proved that AT2R-Exo were more effectively accumulated in the injured carotid artery than EXO and Vehicle-EXO controls. AT2R-EXO treatment could improve blood flow of the injured carotid artery site more effectively. Further analysis revealed that AT2REXO prevents restenosis after carotid artery injury by attenuating the injury-induced neointimal hyperplasia. Our study provides a novel and more efficient exosome for the treatment of restenosis diseases after intervention.
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Traumatismos de las Arterias Carótidas , Exosomas , Animales , Humanos , Hiperplasia/complicaciones , Proliferación Celular , Células Endoteliales , Células Cultivadas , Modelos Animales de Enfermedad , Traumatismos de las Arterias Carótidas/etiología , Traumatismos de las Arterias Carótidas/terapia , Neointima/complicaciones , Neointima/prevención & controlRESUMEN
PURPOSE Despite frequent use of self-expanding stents (SES) in treating obstructive arterial lesions in Takayasu arteritis (TA), spontaneous delayed stent expansion (SDSE) in TA remains unstudied. This study aimed primarily to document and quantify SDSE and secondarily to determine factors that might be associated with this process. METHODS Consecutive TA patients with obstructive arterial lesions undergoing routine percutaneous intervention involving SES use (sized 1:1 with normal vessel diameter but dilated only to 4mm/5mm) were recruited prospectively. Final stent diameters obtained were measured at 1cm intervals along the length of the stent using fluoroscopic images and an indwelling marker catheter. At angiographic follow-up, stent diameters were measured again in identical fashion. Interval change in stent diameter at each point was averaged for each stent. In a small sub-study intravascular ultrasound was used at follow-up to obtain potential mechanistic insights. RESULTS Seventeen TA patients (age 33 ± 13 years, 15 female) had 22 arterial obstructive lesions (16 occlusions, 18 subclavian) treated with one SES each. Follow-up obtained in all patients after 8.7 ± 3.8 months (range 3-18 months) showed interval increase in mean stent diameter of 1.6 ± 0.5 mm, range 0.7-2.8 mm (P < 0.001); 36% of stents achieved 100% of the nominal diameter at follow-up, while 90% of stents achieved ≥90%. The degree of SDSE did not correlate with the segment of artery stented or with TA disease activity at baseline. Intravascular ultrasound in four lesions showed that SDSE was associated with positive medial-adventitial remodelling and that neointimal hyperplasia occurs concurrently, causing in-stent luminal narrowing. CONCLUSION SDSE, to diameters equal or close to nominal, occurs in all stenotic TA lesions treated with SES. The degree of SDSE does not correlate with the segment of artery stented or with TA disease activity at baseline. Preliminary results suggest that the mechanism by which SDSE is accommodated by the arterial wall is by positive medial-adventitial remodelling.
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Arteritis de Takayasu , Humanos , Femenino , Adulto Joven , Adulto , Persona de Mediana Edad , Arteritis de Takayasu/complicaciones , Arteritis de Takayasu/diagnóstico por imagen , Arteritis de Takayasu/cirugía , Resultado del Tratamiento , Stents , Neointima/complicaciones , ArteriasRESUMEN
BACKGROUND: Coronary stenosis can be caused de novo atherosclerosis, in-stent restenosis, and in-stent neoatherosclerosis, three entities that develop from a diverse pathophysiological milieu. OBJECTIVE: This study aims to investigate, using optical coherence tomography (OCT), whether or not coronary lesions related to these processes differ in their local inflammatory profile. METHODS: Retrospective analysis of patients with diagnosed or suspected coronary lesions who had undergone OCT imaging for clinical reasons. Macrophage and intra-plaque neovascularization were assessed by OCT and used as surrogates of local inflammation. A significance level of < 0.05 was adopted as statistically significant. RESULTS: From the 121 lesions, 74 were de novo, 29 were restenosis, and 18 were neoatherosclerosis. Neovascularization was found in 65.8% of de novo, 10.3% in restenosis, and 94.4% in neoatherosclerosis (p<0.01 for all). The volume of neovascularization was different among lesion types (950 vs. 0 vs. 6220, respectively [median values in 1000 x µm3/mm]; p<0.01 for all), which were significantly higher in neoatherosclerosis and lower in restenosis. The presence of macrophages differed among the lesions (95.9% in de novo vs. 6.9% in restenosis vs. 100% in neoatherosclerosis [p<0.01 for all]). Moreover, the intensity of macrophagic infiltration was different among lesion types (2.5 vs. 0.0 vs. 4.5, respectively [median values of macrophage score]; p<0.01 for all), significantly higher in neoatheroscleosis and lower in restenosis. CONCLUSION: When compared using coronary OCT, de novo atherosclerosis, in-stent restenosis, and neoatherosclerosis presented markedly different inflammatory phenotypes.
FUNDAMENTO: A estenose coronária pode ser causada por de novo aterosclerose, reestenose intra-stent e neoaterosclerose intra-stent, três entidades que se desenvolvem a partir de diversos meios fisiopatológicos. OBJETIVOS: Este estudo tem como objetivo investigar, por meio da tomografia de coerência óptica (OCT), se as lesões coronarianas relacionadas a esses processos diferem em seu perfil inflamatório local. MÉTODOS: Análise retrospectiva de pacientes com lesões coronárias diagnosticadas ou suspeitas que realizaram exames de OCT por motivos clínicos. Macrófagos e neovascularização intraplaca foram avaliados por OCT e utilizados como marcadores de inflamação local. O nível de significância < 0,05 foi adotado como estatisticamente significante. RESULTADOS: Das 121 lesões, 74 eram de novo , 29 eram reestenose e 18 eram neoaterosclerose. Neovascularização foi encontrada em 65,8% das de novo , 10,3% na reestenose e 94,4% na neoaterosclerose (p<0,01 para todos). O volume de neovascularização foi diferente entre os tipos de lesão (950 vs. 0 vs. 6.220, respectivamente [valores medianos em 1000 x µm 3 /mm]; p<0,01 para todos), sendo significativamente maior na neoaterosclerose e menor na reestenose. A presença de macrófagos diferiu entre as lesões (95,9% em de novo vs. 6,9% em reestenose vs. 100% em neoaterosclerose [p<0,01 para todos]). Além disso, a intensidade da infiltração macrofágica foi diferente entre os tipos de lesão (2,5 vs. 0,0 vs. 4,5, respectivamente [valores medianos do escore de macrófagos]; p<0,01 para todos), significativamente maior na neoaterosclerose e menor na reestenose. CONCLUSÕES: Quando comparados pela OCT coronariana, de novo , reestenose intra-stent e neoaterosclerose apresentaram fenótipos inflamatórios marcadamente diferentes.
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Aterosclerosis , Reestenosis Coronaria , Stents Liberadores de Fármacos , Enfermedades de las Válvulas Cardíacas , Intervención Coronaria Percutánea , Humanos , Tomografía de Coherencia Óptica/efectos adversos , Tomografía de Coherencia Óptica/métodos , Neointima/diagnóstico por imagen , Neointima/complicaciones , Neointima/patología , Reestenosis Coronaria/diagnóstico por imagen , Reestenosis Coronaria/etiología , Reestenosis Coronaria/patología , Estudios Retrospectivos , Vasos Coronarios/diagnóstico por imagen , Aterosclerosis/diagnóstico por imagen , Aterosclerosis/complicaciones , Stents/efectos adversos , Enfermedades de las Válvulas Cardíacas/patología , Constricción Patológica , Intervención Coronaria Percutánea/efectos adversos , FenotipoRESUMEN
BACKGROUND: Endovascular treatment of atherosclerotic arterial disease exhibits sex differences in clinical outcomes including restenosis. However, sex-specific differences in arterial identity during arterial remodeling have not been described. We hypothesized that sex differences in expression of the arterial determinant erythropoietin-producing hepatocellular receptor interacting protein (Ephrin)-B2 occur during neointimal proliferation and arterial remodeling. METHODS AND RESULTS: Carotid balloon injury was performed in female and male Sprague-Dawley rats without or 14 days after gonadectomy; the left common carotid artery was injured and the right carotid artery in the same animal was used as an uninjured control. Arterial hemodynamics were evaluated in vivo using ultrasonography pre-procedure and post-procedure at 7 and 14 days and wall composition examined using histology, immunofluorescence and Western blot at 14 days after balloon injury. There were no significant baseline sex differences. 14 days after balloon injury, there was decreased neointimal thickness in female rats with decreased smooth muscle cell proliferation and decreased type I and III collagen deposition, as well as decreased TNFα- or iNOS-positive CD68+ cells and increased CD206- or TGM2-positive CD68+ cells. Female rats also showed less immunoreactivity of VEGF-A, NRP1, phosphorylated EphrinB2, and increased Notch1, as well as decreased phosphorylated Akt1, p38 and ERK1/2. These differences were not present in rats pretreated with gonadectomy. CONCLUSIONS: Decreased neointimal thickness in female rats after carotid balloon injury is associated with altered arterial identity that is dependent on intact sex hormones. Alteration of arterial identity may be a mechanism of sex differences in neointimal proliferation after arterial injury.
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Traumatismos de las Arterias Carótidas , Animales , Arterias Carótidas/patología , Traumatismos de las Arterias Carótidas/complicaciones , Traumatismos de las Arterias Carótidas/metabolismo , Traumatismos de las Arterias Carótidas/patología , Modelos Animales de Enfermedad , Femenino , Hiperplasia/patología , Masculino , Neointima/complicaciones , Neointima/metabolismo , Neointima/patología , Ratas , Ratas Sprague-Dawley , Caracteres SexualesRESUMEN
Stents are lifesaving mechanical devices that re-establish essential blood flow to the coronary circulation after significant vessel occlusion due to coronary vessel disease or thrombolytic blockade. Improvements in stent surface engineering over the last 20 years have seen significant reductions in complications arising due to restenosis and thrombosis. However, under certain conditions such as diabetes mellitus (DM), the incidence of stent-mediated complications remains 2-4-fold higher than seen in non-diabetic patients. The stents with the largest market share are designed to target the mechanisms behind neointimal hyperplasia (NIH) through anti-proliferative drugs that prevent the formation of a neointima by halting the cell cycle of vascular smooth muscle cells (VSMCs). Thrombosis is treated through dual anti-platelet therapy (DAPT), which is the continual use of aspirin and a P2Y12 inhibitor for 6-12 months. While the most common stents currently in use are reasonably effective at treating these complications, there is still significant room for improvement. Recently, inflammation and redox stress have been identified as major contributing factors that increase the risk of stent-related complications following percutaneous coronary intervention (PCI). The aim of this review is to examine the mechanisms behind inflammation and redox stress through the lens of PCI and its complications and to establish whether tailored targeting of these key mechanistic pathways offers improved outcomes for patients, particularly those where stent placement remains vulnerable to complications. In summary, our review highlights the most recent and promising research being undertaken in understanding the mechanisms of redox biology and inflammation in the context of stent design. We emphasize the benefits of a targeted mechanistic approach to decrease all-cause mortality, even in patients with diabetes.
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Reestenosis Coronaria , Stents Liberadores de Fármacos , Intervención Coronaria Percutánea , Trombosis , Reestenosis Coronaria/etiología , Stents Liberadores de Fármacos/efectos adversos , Humanos , Inflamación/complicaciones , Neointima/complicaciones , Intervención Coronaria Percutánea/efectos adversos , Stents/efectos adversos , Trombosis/etiologíaRESUMEN
Vascular intimal injury initiates various cardiovascular disease processes. Exposure to subendothelial collagen can cause platelet activation, leading to collagen-activated platelet-derived microvesicles (aPMVs) secretion. In addition, vascular smooth muscle cells (VSMCs) exposed to large amounts of aPMVs undergo abnormal energy metabolism; they proliferate excessively and migrate after the loss of endothelium, eventually contributing to neointimal hyperplasia. However, the roles of aPMVs in VSMC energy metabolism are still unknown. Our carotid artery intimal injury model indicated that platelets adhered to injured blood vessels. In vitro, phosphorylated Pka (cAMP-dependent protein kinase) content was increased in aPMVs. We also found that aPMVs significantly reduced VSMC glycolysis and increased oxidative phosphorylation, and promoted VSMC migration and proliferation by upregulating phosphorylated PRKAA (α catalytic subunit of AMP-activated protein kinase) and phosphorylated FoxO1. Compound C, an inhibitor of PRKAA, effectively reversed the enhancement of cellular function and energy metabolism triggered by aPMVs in vitro and neointimal formation in vivo. We show that aPMVs can affect VSMC energy metabolism through the Pka-PRKAA-FoxO1 signaling pathway and this ultimately affects VSMC function, indicating that the shift in VSMC metabolic phenotype by aPMVs can be considered a potential target for the inhibition of hyperplasia. This provides a new perspective for regulating the abnormal activity of VSMCs after injury.
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Traumatismos de las Arterias Carótidas , Músculo Liso Vascular , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Plaquetas/metabolismo , Traumatismos de las Arterias Carótidas/genética , Traumatismos de las Arterias Carótidas/metabolismo , Movimiento Celular , Proliferación Celular , Células Cultivadas , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Metabolismo Energético , Humanos , Hiperplasia/complicaciones , Hiperplasia/metabolismo , Hiperplasia/patología , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Neointima/complicaciones , Neointima/metabolismo , Neointima/patologíaRESUMEN
BACKGROUND The aim of this study was to compare changes in the extracellular matrix after implantation of a stent that elutes a matrix metalloproteinase (MMP) inhibitor (GM6001); and to determine the effects of the GM6001-eluting stent upon prevention of in-stent restenosis (ISR). MATERIAL AND METHODS We included 48 Guangxi Bama mini-pigs in this study. A GM6001-eluting stent was placed in one iliac artery and a stent that did not elute GM6001 was placed in the contralateral iliac artery. The iliac arteries were removed at 6 hours as well as 1, 7, 14, 56, 84, and 336 days after stent placement. Arteries were analyzed for morphometry, gelatinase content, different phenotypes of vascular smooth muscle cells (VSMCs), collagen content, apoptotic rate, and cell density. RESULTS The vascular lumen areas of the GM6001 group were significantly increased and the neointimal areas were significantly reduced compared with the control group from the 7 days to the 336 days. In the 2 groups, expression of MMP-2 and MMP-9 peaked simultaneously, but GM6001-eluting stents inhibited expression of MMP-2 and MMP-9 in the vascular media and neointima (especially around the struts) significantly. In the GM6001 group, expression of tissue inhibitor of matrix metalloproteinase (TIMP)-1, TIMP-2, myosin heavy chain 10 (MYH-10, marker of the proliferative phenotype of VSMCs), collagen content, percentage of apoptotic cells, and cell density were also decreased significantly compared with those in the control group. CONCLUSIONS Use of GM6001-eluting stents resulted in persistent and potent inhibition of intimal hyperplasia, an increase in luminal area, and no obvious thrombosis in the arteries of the mini-pigs.
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Reestenosis Coronaria/tratamiento farmacológico , Stents Liberadores de Fármacos , Inhibidores de la Metaloproteinasa de la Matriz/uso terapéutico , Animales , Apoptosis , Colágeno/metabolismo , Reestenosis Coronaria/complicaciones , Reestenosis Coronaria/patología , Femenino , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Cadenas Pesadas de Miosina/metabolismo , Neointima/complicaciones , Neointima/patología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Porcinos , Porcinos Enanos , Factores de Tiempo , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/metabolismoRESUMEN
OBJECTIVE: Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are related to in-stent-restenosis (ISR) following percutaneous coronary intervention (PCI). Osteoprotegerin (OPG) has been implicated in various vascular diseases. However, the effects of OPG on ISR and the underlying mechanism remained elusive. We here investigated the association between OPG and ISR, and to demonstrate the role and potential mechanisms of OPG in neointimal hyperplasia. APPROACH AND RESULTS: From 2962 patients who received coronary angiography and follow-up coronary angiography at approximately one year, 291 patients were diagnosed with ISR, and another 291 gender- and age- matched patients without ISR were selected as controls. Serum OPG levels were significantly increased in patients with ISR. Multivariable logistic regression analysis indicated that OPG level was independently associated with the increased risk of ISR. In a mouse femoral artery wire injury model, upregulated OPG was evidenced in vascular tissue after injury. OPG deletion attenuated the vascular injury-induced neointimal hyperplasia and related gene expression in mice. OPG promoted neointimal hyperplasia and human aortic smooth muscle cell (hASMC) proliferation and migration through activation of yes-associated protein (YAP), a major downstream effector of the Hippo signaling pathway, whereas knockdown or inhibition of YAP in hASMCs blunted OPG-induced above effects. Moreover, we found that OPG, as a ligand for integrin αVß3, mediated phosphorylation of focal adhesion kinase (FAK) and actin cytoskeleton reorganization, resulting in YAP dephosphorylation in hASMCs. OPG-dependent YAP and VSMC activation was prevented by treatment with αVß3-blocking antibodies and inhibitors of FAK and actin stress fibers. CONCLUSIONS: Increased serum OPG levels are associated with increased risk of ISR following PCI and OPG could promote neointimal hyperplasia in response to injury through integrin αVß3 mediated FAK and YAP activation, indicating OPG/YAP inhibition might serve as an attractive novel target for the prevention of ISR after PCI.
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Reestenosis Coronaria/complicaciones , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Integrina alfaVbeta3/metabolismo , Neointima/complicaciones , Neointima/patología , Osteoprotegerina/metabolismo , Transducción de Señal , Stents/efectos adversos , Citoesqueleto de Actina/efectos de los fármacos , Citoesqueleto de Actina/metabolismo , Anciano , Animales , Movimiento Celular , Proliferación Celular , Reestenosis Coronaria/sangre , Progresión de la Enfermedad , Femenino , Arteria Femoral/metabolismo , Arteria Femoral/patología , Humanos , Hiperplasia , Incidencia , Modelos Logísticos , Masculino , Ratones Endogámicos C57BL , Análisis Multivariante , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/patología , Neointima/sangre , Osteoprotegerina/sangre , Osteoprotegerina/deficiencia , Fosforilación/efectos de los fármacos , Índice de Severidad de la Enfermedad , Regulación hacia Arriba , Verteporfina/farmacologíaRESUMEN
PURPOSE: To explore the effects of biodegradable magnesium alloy stents (BMAS) on remodeling of vein graft (VG) anastomotic restenosis. MATERIALS AND METHODS: To establish a VG restenosis model, seventy two New Zealand rabbits were randomly divided into three groups according to whether a stent was implanted in the graft vein or not. BMASs and 316L stainless steel stents were implanted in BMAS and 316L groups, respectively, while no stent was implanted in the no-treatment control group (NC group). Loss of lumen diameter in the graft vein was measured in all three groups. Upon harvesting VG segments to evaluate intimal proliferation and re-endothelization, the degradation and biological safety of the stents were observed to explore the effects of BMAS on VG remodeling. RESULTS: Model establishment and stent implantation were successful. The BMAS reduced lumen loss, compared with the control group (0.05±0.34 mm vs. 0.90±0.39 mm, p=0.001), in the early stage. The neointimal area was smaller in the BMAS group than the 316L group after 4 months (4.96±0.66 mm² vs. 6.80±0.69 mm², p=0.017). Re-endothelialization in the BMAS group was better than that in the 316L group (p=0.001). Within 4 months, the BMAS had degraded, and the magnesium was converted to phosphorus and calcium. The support force of the BMAS began to reduce at 2-3 months after implantation, without significant toxic effects. CONCLUSION: BMAS promotes positive remodeling of VG anastomosis and has advantages over the conventional 316L stents in the treatment of venous diseases.
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Aleaciones/farmacología , Materiales Biocompatibles/farmacología , Prótesis Vascular , Reestenosis Coronaria/terapia , Magnesio/farmacología , Stents , Animales , Implantación de Prótesis Vascular , Constricción Patológica , Reestenosis Coronaria/complicaciones , Femenino , Neointima/complicaciones , ConejosRESUMEN
Monounsaturated free fatty acids (FFAs) can serve as a predictive indicator of vascular restenosis following interventional therapy, particularly in individuals with highfat dietinduced type 2 diabetes. However, the pathogenic mechanism remains to be fully elucidated. In the present study, the levels of tyrosine 3monooxygenase/tryptophan 5monooxygenase activation protein ß (YWHAB; also known as 1433ß), in vascular smooth muscle cells (VSMCs) treated with different concentrations of oleic acid (OA) were examined by reverse transcriptionquantitative polymerase chain reaction and western blot analyses. The migration of VSMCs was examined using woundhealing and Transwell migration assays. The protein distribution of Bcell lymphoma 2 (BCL2)associated death promoter (BAD) in VSMCs treated with OA was examined by immunofluorescence and western blot analyses. In in vivo experiments, the carotid artery morphology of rats in different groups was assessed at 14 days postinjury by non-invasive ultrasonographic imaging and confirmed by histological staining. The expression of YWHAB was upregulated by OA in a concentrationdependent manner in VSMCs. In the in vivo experiments, carotid stenosis was more serious among highFFA diabetic rats. However, silencing of YWHAB significantly alleviated carotid neointimal hyperplasia among the diabetic rats with elevated FFA levels. In addition, YWHAB silencing alleviated the migration of OAtreated VSMCs and increased translocation of the BAD protein from the cytoplasm to the mitochondria. In conclusion, the results showed that FFAinduced upregulation of YWHAB was involved in neointimal hyperplasia by enhancing the migration of VSMCs following carotid artery injury. The inhibition of YWHAB may serve as a novel potential pharmacological target for preventing vascular restenosis following interventional therapy in diabetic individuals with high FFA levels.
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Proteínas 14-3-3/genética , Arterias Carótidas/patología , Traumatismos de las Arterias Carótidas/complicaciones , Diabetes Mellitus Experimental/complicaciones , Ácidos Grasos/sangre , Regulación hacia Arriba , Proteínas 14-3-3/metabolismo , Animales , Arterias Carótidas/metabolismo , Traumatismos de las Arterias Carótidas/sangre , Traumatismos de las Arterias Carótidas/genética , Traumatismos de las Arterias Carótidas/metabolismo , Movimiento Celular , Células Cultivadas , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Ácidos Grasos/metabolismo , Silenciador del Gen , Masculino , Neointima/sangre , Neointima/complicaciones , Neointima/genética , Neointima/metabolismo , Ratas Sprague-DawleyRESUMEN
Osthole (7-methoxy-8-isopentenoxy-coumarin), a compound extracted from Cnidiummonnieri (L.) Cusson seeds, has been found to exhibit potent therapeutic effects in cancer due to its ability to inhibit inflammation and cell proliferation. However, its effects on arterial wall hypertrophy-related diseases remain unclear. Therefore, in this study, we aimed to investigate the effects of Osthole on intimal hyperplasia in a rat model of carotid artery balloon injury. We established the balloon-induced carotid artery injury rat model in male Sprague-Dawley rats, after which we administered Osthole (20mg/kg/day or 40mg/kg/day) or volume-matched normal saline orally by gavage for 14 consecutive days. Intimal hyperplasia and the degree of vascular smooth muscle cell proliferation were then evaluated by histopathological examination of the changes in the carotid artery, as well as by examination of proliferating cell nuclear antigen (PCNA) expression. Tumour necrosis factor-É (TNF-α), interleukin-1ß (IL-1ß), transforming growth factor-beta (TGF-ß1) and PCNA mRNA expression levels were examined by real-time RT-PCR, while nuclear factor-κB (NF-κB (p65)), IκB-α, TGF-ß1 and phospho-Smad2 (p-Smad2) protein expression levels were analysed by immunohistochemistry or western blot analysis. We found that Osthole significantly attenuated neointimal thickness and decreased the elevations in PCNA protein expression induced by balloon injury. Moreover, Osthole down-regulated the pro-inflammatory factors TNF-α and IL-1ß and NF-κB (p65), whose expression had been upregulated after balloon injury. Moreover, IκB-α protein expression levels increased following Osthole treatment. In addition, the elevations in TGF-ß1 and p-Smad2 protein expression induced by balloon injury were both significantly attenuated by Osthole administration. We concluded that Osthole significantly inhibited neointimal hyperplasia in balloon-induced rat carotid artery injury and that the mechanism by which this occurs may involve NF-κB, IL-1ß and TNF-É down-regulation, which alleviates the inflammatory response, and TGF-ß1/Smad2 signalling pathway inhibition.
Asunto(s)
Traumatismos de las Arterias Carótidas/patología , Cumarinas/farmacología , Hiperplasia/tratamiento farmacológico , FN-kappa B/metabolismo , Neointima/patología , Proteína Smad2/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Traumatismos de las Arterias Carótidas/complicaciones , Arteria Carótida Común/efectos de los fármacos , Arteria Carótida Común/patología , Cumarinas/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacos , Hiperplasia/complicaciones , Hiperplasia/patología , Masculino , Neointima/complicaciones , Antígeno Nuclear de Célula en Proliferación/genética , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Factores de TiempoRESUMEN
Platelets play an important role in the pathogenesis of vascular remodelling after injury. Junctional adhesion molecule A (JAM-A) was recently described to regulate platelet activation. Specific deletion of JAM-A from platelets resulted in increased reactivity and in accelerated progression of atherosclerosis. The aim of this study was to investigate the specific contribution of platelet-derived JAM-A to neointima formation after vascular injury. Mice with or without platelet-specific (tr)JAM-A-deficiency in an apolipoprotein e (apoe-/- ) background underwent wire-induced injury of the common carotid artery. Ex vivo imaging by two-photon microscopy revealed increased platelet coverage at the site of injury in trJAM-A-deficient mice. Cell recruitment assays showed increased adhesion of monocytic cells to activated JAM-A-deficient platelets than to control platelets. Inhibition of αM ß2 or GPIbα, but not of CD62P, suppressed those differences. Up to 4 weeks after wire injury, intimal neoplasia and neointimal cellular content were analysed. Neointimal lesion area was increased in trJAM-A-/- apoe-/- mice and the lesions showed an increased macrophage accumulation and proliferating smooth muscle cells compared with trJAM-A+/+ apoe-/- littermates 2 weeks, but not 4 weeks after injury. Re-endothelialization was decreased in trJAM-A-/- apoe-/- mice compared with controls 2 weeks after injury, yet it was complete in both groups after 4 weeks. A platelet gain of function by deletion of JAM-A accelerates neointima formation only during earlier phases after vascular injury, through an increased recruitment of mononuclear cells. Thus, the contribution of platelets might become less important when neointima formation progresses to later stages.
Asunto(s)
Apolipoproteínas E/genética , Aterosclerosis/genética , Traumatismos de las Arterias Carótidas/genética , Moléculas de Adhesión Celular/genética , Hiperlipidemias/genética , Neointima/genética , Receptores de Superficie Celular/genética , Animales , Apolipoproteínas E/deficiencia , Aterosclerosis/complicaciones , Aterosclerosis/metabolismo , Aterosclerosis/patología , Plaquetas/metabolismo , Plaquetas/patología , Arterias Carótidas/metabolismo , Arterias Carótidas/patología , Traumatismos de las Arterias Carótidas/complicaciones , Traumatismos de las Arterias Carótidas/metabolismo , Traumatismos de las Arterias Carótidas/patología , Adhesión Celular , Moléculas de Adhesión Celular/deficiencia , Femenino , Regulación de la Expresión Génica , Hiperlipidemias/complicaciones , Hiperlipidemias/metabolismo , Hiperlipidemias/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/metabolismo , Monocitos/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Neointima/complicaciones , Neointima/metabolismo , Neointima/patología , Receptores de Superficie Celular/deficiencia , Transducción de Señal , Remodelación Vascular/genéticaRESUMEN
BACKGROUND: Neointimal hyperplasia is a common cause of vein graft failure resulting from luminal narrowing and occlusion. Cilostazol is a U.S. Food and Drug Administration-approved phosphodiesterase III and platelet aggregation inhibitor commonly used in peripheral vascular disease. The authors studied whether topical cilostazol treatment at the time of vein grafting helps limit the development of neointimal hyperplasia in a rat model. METHODS: Six experimental rats and six control rats underwent interposition vein grafting into the femoral artery, followed by a single topical dose of cilostazol applied around the vein graft in the experimental animals. After 4 weeks, grafts were harvested and underwent histologic staining of axial sections to visualize intima thickness and elastin/myocyte content. Quantification was performed to assess total intima area. The intima-to-media and the intima-to-sum of intima and media ratios were determined to control for discrepancies in overall graft size. RESULTS: Cilostazol-treated grafts had a thinner intima layer with less myocyte content compared with control grafts, amounting to an 82 percent decrease in total intima area compared with controls. A similar trend was seen even after controlling for overall graft size, with 85 and 76 percent reductions seen in intima-to-media and intima-to-sum of intima and media ratios, respectively. CONCLUSIONS: A single intraoperative dose of cilostazol applied locally significantly reduced intima size and smooth muscle content in rat interposition vein grafts examined 4 weeks postoperatively. A topical dose of cilostazol at surgery may therefore be helpful in controlling neointimal hyperplasia and reducing the need for systemic medications to prolong vein graft patency.
Asunto(s)
Oclusión de Injerto Vascular/prevención & control , Neointima/prevención & control , Inhibidores de Agregación Plaquetaria/uso terapéutico , Tetrazoles/uso terapéutico , Venas/trasplante , Administración Tópica , Animales , Cilostazol , Oclusión de Injerto Vascular/etiología , Hiperplasia/etiología , Hiperplasia/prevención & control , Neointima/complicaciones , Neointima/patología , Ratas , Ratas Sprague-Dawley , Resultado del Tratamiento , Venas/patologíaRESUMEN
Neoatherosclerosis is one of the multiple mechanisms that cause stent thrombosis, which is one of the rare but severe complications of drug-eluting stent implantation. This case study highlights the use of optical coherence tomography in identifying the precise mechanism of the stent thrombosis, which helped guide the appropriate intervention.
Asunto(s)
Enfermedad de la Arteria Coronaria/complicaciones , Reestenosis Coronaria/patología , Trombosis Coronaria/patología , Stents Liberadores de Fármacos/efectos adversos , Neointima/complicaciones , Tomografía de Coherencia Óptica , Adulto , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/patología , Reestenosis Coronaria/diagnóstico , Reestenosis Coronaria/prevención & control , Trombosis Coronaria/diagnóstico , Trombosis Coronaria/prevención & control , Humanos , Masculino , Neointima/diagnóstico por imagen , Neointima/patología , Cooperación del Paciente , Educación del Paciente como Asunto , Inhibidores de Agregación Plaquetaria/uso terapéutico , Resultado del TratamientoRESUMEN
Acute myocardial infarction (AMI) represents one of the major mortality causes in the world. Treatment of AMI is widely known; however, in developing countries some medications are not so easily available yet. We present a case of a 49-year-old black male patient who suffered an AMI and 2 weeks after stent angioplasty evolved to a new ischaemic episode with a stent thrombosis. The patient did not use the prescribed medications.
Asunto(s)
Reestenosis Coronaria/complicaciones , Oclusión de Injerto Vascular/complicaciones , Infarto del Miocardio/etiología , Neointima/complicaciones , Stents , Reestenosis Coronaria/prevención & control , Oclusión de Injerto Vascular/prevención & control , Humanos , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Infarto del Miocardio/prevención & control , Inhibidores de Agregación Plaquetaria/uso terapéuticoRESUMEN
The main pathologenesis of vein graft restenosis is neointimal hyperplasia associated with vascular smooth muscle cell migration and proliferation. Gene therapy offers a novel treatment method for reducing or delaying early thrombosis, intimal hyperplasia, and late atherosclerosis. In this review, we will (1) describe sequential pathologies of vein graft disease; (2) summarize the applications of gene therapy in vein graft restenosis; and (3) discuss novel gene therapy for vein graft failure.