RESUMO
Total neointima implantation (patch neointima technique + triple-branched stent graft placement) has been performed in proximal aortic repair for acute type A aortic dissection (ATAAD) for more than 10 years at a center. However, there is no report on the mid-term outcomes with a control group of the surgical procedure. Consequently, the authors aimed to evaluate the safety and efficacy of this technique in this study. Patients who underwent the total neointima implantation were classified as Group A, and those who underwent the conventional aortic root reconstruction with the "sandwich" technique and the total aortic arch replacement were classified as Group B. Furthermore, the authors described the preoperative characteristics, operative data, and patient outcomes. Group A patients experienced a shorter surgery duration, lower volumes of perioperative bleeding, and fewer red blood cell transfusions. The incidence of neurological complications was significantly reduced in Group A. All patients maintained a normal range of proximal aortic sizes after surgery. Kaplan-Meier analysis revealed no significant differences between the patients in the two groups regarding cumulative mortality and the incidence of moderate-to-severe aortic insufficiency. In well-selected patients, total neointima implantation is an alternative procedure for the surgical repair of ATAAD.
Assuntos
Aneurisma da Aorta Torácica , Dissecção Aórtica , Implante de Prótese Vascular , Hipertensão , Humanos , Aneurisma da Aorta Torácica/etiologia , Aneurisma da Aorta Torácica/cirurgia , Aorta Torácica/cirurgia , Implante de Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/métodos , Neointima/etiologia , Neointima/cirurgia , Hipertensão/etiologia , Dissecção Aórtica/cirurgia , Stents , Resultado do Tratamento , Estudos RetrospectivosRESUMO
Cardiac allograft vasculopathy (CAV) causes late graft failure and mortality after heart transplantation. Donor-specific antibodies (DSAs) lead to chronic endothelial cell injury, inflammation, and arterial intimal thickening. In this study, GeoMx digital spatial profiling was used to analyze arterial areas of interest (AOIs) from CAV+DSA+ rejected cardiac allografts (N = 3; 22 AOIs total). AOIs were categorized based on CAV neointimal thickening and underwent whole transcriptome and protein profiling. By comparing our transcriptomic data with that of healthy control vessels of rapid autopsy myocardial tissue, we pinpointed specific pathways and transcripts indicative of heightened inflammatory profiles in CAV lesions. Moreover, we identified protein and transcriptomic signatures distinguishing CAV lesions exhibiting low and high neointimal lesions. AOIs with low neointima showed increased markers for activated inflammatory infiltrates, endothelial cell activation transcripts, and gene modules involved in metalloproteinase activation and TP53 regulation of caspases. Inflammatory and apoptotic proteins correlated with inflammatory modules in low neointima AOIs. High neointima AOIs exhibited elevated TGFß-regulated transcripts and modules enriched for platelet activation/aggregation. Proteins associated with growth factors/survival correlated with modules enriched for proliferation/repair in high neointima AOIs. Our findings reveal novel insight into immunological mechanisms mediating CAV pathogenesis.
Assuntos
Rejeição de Enxerto , Transplante de Coração , Transplante de Coração/efeitos adversos , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/patologia , Rejeição de Enxerto/imunologia , Humanos , Masculino , Aloenxertos , Isoanticorpos/imunologia , Pessoa de Meia-Idade , Feminino , Transcriptoma , Neointima/patologia , Neointima/imunologia , Neointima/etiologia , Sobrevivência de Enxerto/imunologia , Prognóstico , Seguimentos , Perfilação da Expressão Gênica , Biomarcadores/metabolismo , Doadores de Tecidos , Doenças Vasculares/etiologia , Doenças Vasculares/imunologia , Doenças Vasculares/patologia , MultiômicaRESUMO
OBJECTIVE: This pilot study aimed to observe intimal injuries related to stent retrieval in the iliac artery of a canine. BACKGROUND: In-stent restenosis remains challenging owing to permanent stent implantation. A retrievable stent may be alternative for intervention without permanent residue. METHODS: Five retrievable stents with point-to-point overlapped double-layer scaffolds were deployed into the iliac arteries and retrieved on days 14, 21, 28, 35, and 42 from five canines. RESULTS: Arterial diameter decreased by 9-10% before retrieval and 15% on day 14 after retrieval. In the 14-day-stent, the stent surface was clean without visible fibrin. In the 28-day-stent, the overlay was mainly composed of fibrin and fibroblasts. The proliferation of smooth muscle cells has not yet been observed with α-smooth muscle actin staining. In the 42-day-stent, endothelial and smooth muscle cells decreased under the struts, and the internal elastic lamina was interrupted segmentally. Neointima formation involves fibroblasts and smooth muscle cells. Neointimal thickness was negatively correlated with strut space. Stent traces on the artery wall tended to be flat at a follow-up14 days after retrieval. The primary intima was completely covered by neointima. Two stents could not be retrieved because of in-stent thrombosis or capture loss. CONCLUSIONS: The stent was covered mainly by depositional fibrin after 28 days and by typical neointima after 42 days. The stent retrieval procedure did not induce injury to vascular smooth muscle, and the intima repair was performed 14 days after stent retrieval.
Assuntos
Espessura Intima-Media Carotídea , Neointima , Animais , Cães , Neointima/etiologia , Projetos Piloto , Stents/efeitos adversos , FibrinaRESUMO
Titanium alloys have traditionally been used in blood-contacting cardiovascular devices, including left ventricular assist devices (LVADs). However, titanium surfaces are susceptible to adverse coagulation, leading to thrombogenesis and stroke. To improve hemocompatibility, LVAD manufacturers introduced powder sintering on blood-wetted surfaces in the 1980s to induce endothelialization. This technique has been employed in multiple contemporary LVADs on the pump housing, as well as the interior and exterior of the inflow cannula. Despite the wide adoption of sintered titanium, reported biologic response over the past several decades has been highly variable and apparently unpredictable-including combinations of neointima, pseudoneoimtima, thrombus, and pannus. We present a history of sintered titanium used in LVAD, a review of accumulated clinical outcomes, and a synopsis of gross appearance and composition of various depositions found clinically and in animal studies, which is unfortunately confounded by the variability and inconsistency in terminology. Therefore, this review endeavors to introduce a unified taxonomy to harmonize published observations of biologic response to sintered titanium in LVADs. From these data, we are able to deduce the natural history of the biologic response to sintered titanium, toward development of a deterministic model of the genesis of a hemocompatible neointima.
Assuntos
Produtos Biológicos , Coração Auxiliar , Trombose , Animais , Titânio , Pannus , Neointima/etiologia , Trombose/etiologia , Coração Auxiliar/efeitos adversosRESUMO
BACKGROUND: Diabetes mellitus (DM) is an important predictor of neointimal hyperplasia (NIH) and adverse clinical outcomes after percutaneous coronary intervention (PCI). LABR-312, a novel intravenous formulation of liposomal alendronate, has been shown in animal models to decrease NIH at vascular injury sites and around stent struts. The aim of the Biorest Liposomal Alendronate Administration for Diabetic Patients Undergoing Drug-Eluting Stent Percutaneous Coronary Intervention trial was to assess the safety, effectiveness, and dose response of LABR-312 administered intravenously at the time of PCI withDES in reducing NIH as measured by optical coherence tomography postprocedure in patients with DM. METHODS: Patients with DM were randomized to a bolus infusion of LABR-312 vs placebo at the time of PCI. Dose escalation of LABR-312 in the study arm was given: 0.01 mg, 0.03 mg, and 0.08 mg. The primary endpoint was the in-stent %NIH volume at 9 months as measured by optical coherence tomography. RESULTS: From September 2016 to December 2017, 271 patients with DM undergoing PCI were enrolled; 136 patients were randomized to LABR-312 infusion and 135 patients were randomized to placebo. At 9-month follow-up, no difference was seen in the primary endpoint of %NIH between LABR-312 and placebo (13.3% ± 9.2 vs 14.6% ± 8.5, P = .35). No differences were present with the varying LABR-312 doses. Clinical outcomes at 9 months were similar between groups. CONCLUSIONS: Among patients with DM undergoing PCI with drug-eluting stents, a bolus of LABR-312 injected systematically at the time of intervention did not result in a lower rate in-stent %NIH volume at 9-month follow-up.
Assuntos
Doença da Artéria Coronariana , Diabetes Mellitus , Stents Farmacológicos , Intervenção Coronária Percutânea , Alendronato , Angiografia Coronária/métodos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/cirurgia , Humanos , Neointima/etiologia , Intervenção Coronária Percutânea/métodos , Tomografia de Coerência Óptica , Resultado do TratamentoRESUMO
BACKGROUND: Smooth muscle cells (SMCs) are the main driver of neointima formation and restenosis following vascular injury. In animal models, endothelial progenitor cells (EPCs) accelerate endothelial regeneration and reduce neointima formation after arterial injury; however, EPC-capture stents do not reduce target vessel failure compared with conventional stents. Here we examined the influence of EPCs on features of SMCs pivotal for their impact on injury-induced neointima formation including proliferation, migration, and phenotype switch. METHODS AND RESULTS: EPCs, their conditioned medium, and EPC-derived microparticles induced proliferation of SMCs while limiting their apoptosis. In transwell membrane experiments and scratch assays, EPCs stimulated migration of SMCs and accelerated their recovery from scratch-induced injury. Treatment of SMCs with an EPC-derived conditioned medium or microparticles triggered transformation of SMCs toward a synthetic phenotype. However, co-cultivation of EPCs and SMCs enabling direct cell-cell contacts preserved their original phenotype and protected from the transformative effect of SMC cholesterol loading. Adhesion of EPCs to SMCs was stimulated by SMC injury and reduced by blocking CXCR2 and CCR5. Interaction of EPCs with SMCs modulated their secretory products and synergistically increased the release of selected chemokines. Following carotid wire injury in athymic mice, injection of EPCs resulted not only in reduced neointima formation but also in altered cellular composition of the neointima with augmented accumulation of SMCs. CONCLUSION: EPCs stimulate proliferation and migration of SMCs and increase their neointimal accumulation following vascular injury. Furthermore, EPCs context-dependently modify the SMC phenotype with protection from the transformative effect of cholesterol when a direct cell-cell contact is established.
Assuntos
Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Células Progenitoras Endoteliais , Neointima , Receptores de Interleucina-8B/metabolismo , Regeneração/fisiologia , Lesões do Sistema Vascular , Adaptação Fisiológica/fisiologia , Animais , Apoptose , Artérias/lesões , Artérias/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Células Progenitoras Endoteliais/patologia , Células Progenitoras Endoteliais/fisiologia , Camundongos , Miócitos de Músculo Liso , Neointima/etiologia , Neointima/metabolismo , Neointima/patologia , Neointima/prevenção & controle , Receptores CCR5/metabolismo , Transdução de Sinais/fisiologia , Lesões do Sistema Vascular/metabolismo , Lesões do Sistema Vascular/patologiaRESUMO
AIM: To evaluate healing response at strut-level and cross-section level after implanting an ultra-thin strut, everolimus-eluting stent with biodegradable polymer (Tetrilimus) using optical coherence tomography (OCT) at 3 and 6 months. METHODS: This was prospective, multi-centre, single-arm, and investigator-initiated study performed at seven Indian sites between January, 2017 and September, 2018. OCT evaluations were performed in 57 patients who underwent Tetrilimus stent implantation. Follow-up OCT was scheduled at 3 months for first 16 patients and at 6 months for 41 patients. Primary outcomes included degree of strut coverage, malapposition and thickness of neointimal hyperplasia (NIH) over covered struts. RESULTS: Sixty one Tetrilimus stents were implanted to treat 59 lesions in 57 patients. Paired (baseline and follow-up) OCT data was available for 12 patients and 30 patients at 3 and 6 months, respectively. At 3 months, rapid early healing was indicated by 95.48% covered struts per lesion with very low (0.11 ± 0.06 mm) NIH. At 6 months, NIH accumulation was greater (0.21 ± 0.07 mm) as compared to 3 months. 99.77% of struts per lesion were covered at 6 months. There was a very symmetrical healing as shown by very low eccentricity index. There was no difference in vascular healing between stents with small to moderate size vessels (≤3.00 mm) and large size vessels (>3.00 mm). CONCLUSION: Present study demonstrated nearly complete endothelization and low NIH accumulation at 3 and 6 months following implantation of ultra-thin strut everolimus-eluting biodegradable polymer-coated Tetrilimus stent. Moreover, though being an ultra-thin strut stent, there was no difference in vascular healing and eccentricity after implantation of the Tetrilimus stents with smaller and larger diameters.
Assuntos
Doença da Artéria Coronariana , Stents Farmacológicos , Intervenção Coronária Percutânea , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/terapia , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/patologia , Everolimo/efeitos adversos , Humanos , Neointima/etiologia , Neointima/patologia , Intervenção Coronária Percutânea/efeitos adversos , Estudos Prospectivos , Sirolimo , Stents , Tomografia de Coerência Óptica , Resultado do TratamentoRESUMO
Mutations in the NF1 tumor suppressor gene are linked to arteriopathy. Nf1 heterozygosity (Nf1+/-) results in robust neointima formation, similar to humans, and myeloid-restricted Nf1+/- recapitulates this phenotype via MEK-ERK activation. Here we define the contribution of myeloid subpopulations to NF1 arteriopathy. Neutrophils from WT and Nf1+/- mice were functionally assessed in the presence of MEK and farnesylation inhibitors in vitro and neutrophil recruitment to lipopolysaccharide was assessed in WT and Nf1+/- mice. Littermate 12-15 week-old male wildtype and Nf1+/- mice were subjected to carotid artery ligation and provided either a neutrophil depleting antibody (1A8), liposomal clodronate to deplete monocytes/macrophages, or PD0325901 and neointima size was assessed 28 days after injury. Bone marrow transplant experiments assessed monocyte/macrophage mobilization during neointima formation. Nf1+/- neutrophils exhibit enhanced proliferation, migration, and adhesion via p21Ras activation of MEK in vitro and in vivo. Neutrophil depletion suppresses circulating Ly6Clow monocytes and enhances neointima size, while monocyte/macrophage depletion and deletion of CCR2 in bone marrow cells abolish neointima formation in Nf1+/- mice. Taken together, these findings suggest that neurofibromin-MEK-ERK activation in circulating neutrophils and monocytes during arterial remodeling is nuanced and points to important cross-talk between these populations in the pathogenesis of NF1 arteriopathy.
Assuntos
Lesões das Artérias Carótidas/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Células Progenitoras Mieloides/patologia , Neointima/patologia , Neurofibromatose 1/patologia , Neurofibromina 1/fisiologia , Receptores CCR2/fisiologia , Animais , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Lesões das Artérias Carótidas/etiologia , Lesões das Artérias Carótidas/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Monócitos/patologia , Células Progenitoras Mieloides/metabolismo , Neointima/etiologia , Neointima/metabolismo , Neurofibromatose 1/etiologia , Neurofibromatose 1/metabolismoRESUMO
Restenosis is a common vascular complication after balloon angioplasty. Catheter balloon inflation-induced transient ischemia (hypoxia) of local arterial tissues plays a pathological role in neointima formation. Phosphoglycerate kinase 1 (PGK1), an adenosine triphosphate (ATP)-generating glycolytic enzyme, has been reported to associate with cell survival and can be triggered under hypoxia. The purposes of this study were to investigate the possible role and regulation of PGK1 in vascular smooth muscle cells (VSMCs) and balloon-injured arteries under hypoxia. Neointimal hyperplasia was induced by a rat carotid artery injury model. The cellular functions and regulatory mechanisms of PGK1 in VSMCs were investigated using small interfering RNAs (siRNAs), chemical inhibitors, or anaerobic cultivation. Our data indicated that protein expression of PGK1 can be rapidly induced at a very early stage after balloon angioplasty, and the silencing PGK1-induced low cellular energy circumstance resulted in the suppressions of VSMC proliferation and migration. Moreover, the experimental results demonstrated that blockage of PDGF receptor-ß (PDGFRB) or its downstream pathway, the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) axis, effectively reduced hypoxia-induced factor-1 (HIF-1α) and PGK1 expressions in VSMCs. In vivo study evidenced that PGK1 knockdown significantly reduced neointima hyperplasia. PGK1 was expressed at the early stage of neointimal formation, and suppressing PGK1 has a potential beneficial effect for preventing restenosis.
Assuntos
Angioplastia com Balão/efeitos adversos , Lesões das Artérias Carótidas/terapia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Neointima/patologia , Fosfoglicerato Quinase/metabolismo , Animais , Movimento Celular , Células Cultivadas , Masculino , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Neointima/etiologia , Neointima/metabolismo , Fosfoglicerato Quinase/genética , Ratos , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
Accumulation of vascular smooth muscle cells (VSMCs) is a hallmark of multiple vascular pathologies, including following neointimal formation after injury and atherosclerosis. However, human VSMCs in advanced atherosclerotic lesions show reduced cell proliferation, extensive and persistent DNA damage, and features of premature cell senescence. Here, we report that stress-induced premature senescence (SIPS) and stable expression of a telomeric repeat-binding factor 2 protein mutant (TRF2T188A) induce senescence of human VSMCs, associated with persistent telomeric DNA damage. VSMC senescence is associated with formation of micronuclei, activation of cGAS-STING cytoplasmic sensing, and induction of multiple pro-inflammatory cytokines. VSMC-specific TRF2T188A expression in a multicolor clonal VSMC-tracking mouse model shows no change in VSMC clonal patches after injury, but an increase in neointima formation, outward remodeling, senescence and immune/inflammatory cell infiltration or retention. We suggest that persistent telomere damage in VSMCs inducing cell senescence has a major role in driving persistent inflammation in vascular disease.
Assuntos
Aterosclerose/patologia , Senescência Celular , Inflamação/patologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Neointima/patologia , Telômero/patologia , Animais , Aterosclerose/etiologia , Aterosclerose/metabolismo , Proliferação de Células , Células Cultivadas , Dano ao DNA , Modelos Animais de Doenças , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Microfilamentos/fisiologia , Proteínas Musculares/fisiologia , Músculo Liso Vascular/imunologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/imunologia , Miócitos de Músculo Liso/metabolismo , Neointima/etiologia , Neointima/metabolismo , Telômero/genética , Proteína 2 de Ligação a Repetições Teloméricas/metabolismoRESUMO
Rapidly proliferating cells such as vascular smooth muscle cells (VSMCs) require metabolic programs to support increased energy and biomass production. Thus, targeting glutamine metabolism by inhibiting glutamine transport could be a promising strategy for vascular disorders such as atherosclerosis, stenosis, and restenosis. V-9302, a competitive antagonist targeting the glutamine transporter, has been investigated in the context of cancer; however, its role in VSMCs is unclear. Here, we examined the effects of blocking glutamine transport in fetal bovine serum (FBS)- or platelet-derived growth factor (PDGF)-stimulated VSMCs using V-9302. We found that V-9302 inhibited mTORC1 activity and mitochondrial respiration, thereby suppressing FBS- or PDGF-stimulated proliferation and migration of VSMCs. Moreover, V-9302 attenuated carotid artery ligation-induced neointima in mice. Collectively, the data suggest that targeting glutamine transport using V-9302 is a promising therapeutic strategy to ameliorate occlusive vascular disease.
Assuntos
Movimento Celular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Neointima/tratamento farmacológico , Sistema A de Transporte de Aminoácidos/antagonistas & inibidores , Sistema A de Transporte de Aminoácidos/metabolismo , Animais , Artérias Carótidas/cirurgia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Respiração Celular/efeitos dos fármacos , Células Cultivadas , Ligadura , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Músculo Liso Vascular/metabolismo , Neointima/etiologia , Neointima/patologia , Fator de Crescimento Derivado de Plaquetas/farmacologia , Ratos Sprague-Dawley , Soroalbumina Bovina/farmacologiaRESUMO
Pathological changes after third-generation drug-eluting stent implantation remain unclear. We compared the tissue responses of coronary arteries after the implantation of third-generation abluminal biodegradable-polymer everolimus-eluting stent (3rd EES) and second-generation durable-polymer EES (2nd EES) using autopsy specimens and an atherosclerotic porcine model. We compared the histology of stented coronary arteries obtained by autopsy performed 1-10 months after 3rd EES (n (number of cases) = 4, stent-implanted period of 3-7 months) and 2nd EES (n (number of cases) = 9, stent-implanted period of 1-10 months) implantations. The ratio of covered stent struts was higher with 3rd EESs than with 2nd EESs (3rd; 0.824 ± 0.032 vs. 2nd; 0.736 ± 0.022, p = 0.035). Low-density lipoprotein receptor knockout minipigs were stented with 3rd or 2nd EES in the coronary arteries and the stented regions were investigated. The fibrin deposition around the 2nd EES was more prominent. Additionally, higher density of smooth muscle cells was confirmed after the 3rd EES implantation. Pathological examination after the 3rd EES demonstrated a combination of less fibrin deposition and more rapid acquisition of well-developed neointima as compared to the 2nd EES at autopsy and the atherosclerotic porcine model.
Assuntos
Doença da Artéria Coronariana/cirurgia , Modelos Animais de Doenças , Stents Farmacológicos/efeitos adversos , Stents Farmacológicos/classificação , Everolimo/administração & dosagem , Neointima/etiologia , Intervenção Coronária Percutânea/efeitos adversos , Porco Miniatura/cirurgia , Suínos/cirurgia , Implantes Absorvíveis/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Animais , Animais Geneticamente Modificados , Autopsia , Vasos Coronários/patologia , Vasos Coronários/cirurgia , Feminino , Fibrina/metabolismo , Técnicas de Inativação de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Neointima/metabolismo , Placa Aterosclerótica/cirurgia , Desenho de Prótese , Receptores de LDL/genética , Resultado do TratamentoRESUMO
BACKGROUND: Arteriovenous fistula (AVF) is the most common vascular access for patients undergoing hemodialysis (HD). Neointimal hyperplasia (NIH) might be a potential mechanism of AVF dysfunction. Retinol-binding protein 4 (RBP4) may play an important role in the pathogenesis of NIH. The aim of this study was to investigate whether AVF dysfunction is associated with serum concentrations of RBP4 in HD subjects. METHODS: A cohort of 65 Chinese patients undergoing maintenance HD was recruited between November 2017 and June 2019. The serum concentrations of RBP4 of each patient were measured with the ELISA method. Multivariate logistic regression was used to analyze data on demographics, biochemical parameters, and serum RBP4 level to predict AVF dysfunction events. The cutoff for serum RBP4 level was derived from the highest score obtained on the Youden index. Survival data were analyzed with the Cox proportional hazards regression analysis and Kaplan-Meier method. RESULTS: Higher serum RBP4 level was observed in patients with AVF dysfunction compared to those without AVF dysfunction events (174.3 vs. 168.4 mg/L, p = 0.001). The prevalence of AVF dysfunction events was greatly higher among the high RBP4 group (37.5 vs. 4.88%, p = 0.001). In univariate analysis, serum RBP4 level was statistically significantly associated with the risk of AVF dysfunction (OR = 1.015, 95% CI 1.002-1.030, p = 0.030). In multivariate analysis, each 1.0 mg/L increase in RBP4 level was associated with a 1.023-fold-increased risk of AVF dysfunction (95% CI for OR: 1.002-1.045; p = 0.032). The Kaplan-Meier survival analysis indicated that the incidence of AVF dysfunction events in the high RBP4 group was significantly higher than that in the low-RBP4 group (p = 0.0007). Multivariate Cox regressions demonstrated that RBP4 was an independent risk factor for AVF dysfunction events in HD patients (HR = 1.015, 95% CI 1.001-1.028, p = 0.033). CONCLUSIONS: HD patients with higher serum RBP4 concentrations had a relevant higher incidence of arteriovenous dysfunction events. Serum RBP4 level was an independent risk factor for AVF dysfunction events in HD patients.
Assuntos
Fístula Arteriovenosa/sangue , Diálise Renal , Proteínas Plasmáticas de Ligação ao Retinol/análise , Idoso , Fístula Arteriovenosa/etiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neointima/sangue , Neointima/etiologia , Estudos Prospectivos , Diálise Renal/efeitos adversos , Fatores de RiscoRESUMO
BACKGROUND: The mechanism of vascular remodelling in pulmonary arterial hypertension (PAH) remains unclear. Hence, defining the origin of cells constituting intractable vascular lesions in PAH is expected to facilitate therapeutic progress. Herein, we aimed to evaluate the origin of intractable vascular lesions in PAH rodent models via bone marrow (BM) and orthotopic lung transplantation (LT). METHODS: To trace BM-derived cells, we prepared chimeric rats transplanted with BM cells from green fluorescent protein (GFP) transgenic rats. Male rats were transplanted with lungs obtained from female rats and vice versa. Pulmonary hypertension was induced in the transplanted rats via Sugen5416 treatment and subsequent chronic hypoxia (Su/Hx). RESULTS: In the chimeric Su/Hx models, GFP-positive cells were observed in the pulmonary vascular area. Moreover, the right ventricular systolic pressure was significantly lower compared with wild-type Su/Hx rats without BM transplantation (P = 0.009). PAH suppression was also observed in rats that received allograft transplanted BM transplantation. In male rats that received LT and Su/Hx, BM-derived cells carrying the Y chromosome were also detected in neointimal occlusive lesions of the transplanted lungs received from female rats. CONCLUSIONS: BM-derived cells participate in pulmonary vascular remodelling in the Su/Hx rat model, whereas BM transplantation may contribute to suppression of development of PAH.
Assuntos
Células da Medula Óssea , Transplante de Medula Óssea/métodos , Rastreamento de Células/métodos , Hipóxia , Pulmão , Hipertensão Arterial Pulmonar , Remodelação Vascular/fisiologia , Inibidores da Angiogênese/farmacologia , Animais , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Modelos Animais de Doenças , Feminino , Hipóxia/complicações , Hipóxia/metabolismo , Indóis/farmacologia , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Neointima/etiologia , Neointima/fisiopatologia , Hipertensão Arterial Pulmonar/etiologia , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/patologia , Pirróis/farmacologia , Ratos , Quimeras de Transplante , Remodelação Vascular/efeitos dos fármacosRESUMO
The excessive proliferation and migration of smooth muscle cells (SMCs) play an important role in restenosis following percutaneous coronary interventions. MicroRNAs are able to target various genes and involved in the regulation of diverse cellular processes including cell growth and proliferation. In this study we investigated whether and how MicroRNAs regulated vascular SMC proliferation and vascular remodeling following carotid artery injury in mice. We showed that carotid artery injury-induced neointimal formation was remarkably ameliorated in microRNA (miR)-302 heterozygous mice and SMC-specific miR-302 knockout mice. In contrast, delivery of miR-302a adenovirus to the injured carotid artery enhanced neointimal formation. Upregulation of miR-302a enhanced the proliferation and migration of mouse aorta SMC (MASMC) in vitro by promoting cell cycle transition, whereas miR-302a inhibition caused the opposite results. Moreover, miR-302a promoted Akt activation by corporately decreasing Akt expression and increasing Akt phosphorylation in MASMCs. Application of the Akt inhibitor GSK690693 (5 µmol/L) counteracted the functions of miR-302a in promoting MASMC proliferation and migration. We further revealed that miR-302a directly targeted at the 3' untranslated region of PH domain and leucine rich repeat protein phosphatase 2 (PHLPP2) and negatively regulated PHLPP2 expression. Restoration of PHLPP2 abrogated the effects of miR-302a on Akt activation and MASMC motility. Furthermore, knockdown of PHLPP2 largely abolished the inhibition of neointimal formation that was observed in miR-302 heterozygous mice. Our data demonstrate that miR-302a exacerbates SMC proliferation and restenosis through increasing Akt signaling by targeting PHLPP2.
Assuntos
MicroRNAs/metabolismo , Miócitos de Músculo Liso/metabolismo , Neointima/etiologia , Fosfoproteínas Fosfatases/metabolismo , Transdução de Sinais/fisiologia , Remodelação Vascular/fisiologia , Animais , Lesões das Artérias Carótidas/complicações , Lesões das Artérias Carótidas/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/fisiologia , Feminino , Técnicas de Inativação de Genes , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Background Failure rates after revascularization surgery remain high, both in vein grafts (VG) and arterial interventions. One promising approach to improve outcomes is endogenous upregulation of the gaseous transmitter-molecule hydrogen sulfide, via short-term dietary restriction. However, strict patient compliance stands as a potential translational barrier in the vascular surgery patient population. Here we present a new therapeutic approach, via a locally applicable gel containing the hydrogen sulfide releasing prodrug (GYY), to both mitigate graft failure and improve arterial remodeling. Methods and Results All experiments were performed on C57BL/6 (male, 12 weeks old) mice. VG surgery was performed by grafting a donor-mouse cava vein into the right common carotid artery of a recipient via an end-to-end anastomosis. In separate experiments arterial intimal hyperplasia was assayed via a right common carotid artery focal stenosis model. All mice were harvested at postoperative day 28 and artery/graft was processed for histology. Efficacy of hydrogen sulfide was first tested via GYY supplementation of drinking water either 1 week before VG surgery (pre-GYY) or starting immediately postoperatively (post-GYY). Pre-GYY mice had a 36.5% decrease in intimal/media+adventitia area ratio compared with controls. GYY in a 40% Pluronic gel (or vehicle) locally applied to the graft/artery had decreased intimal/media area ratios (right common carotid artery) and improved vessel diameters. GYY-geltreated VG had larger diameters at both postoperative days 14 and 28, and a 56.7% reduction in intimal/media+adventitia area ratios. Intimal vascular smooth muscle cell migration was decreased 30.6% after GYY gel treatment, which was reproduced in vitro. Conclusions Local gel-based treatment with the hydrogen sulfide-donor GYY stands as a translatable therapy to improve VG durability and arterial remodeling after injury.
Assuntos
Gasotransmissores/uso terapêutico , Sulfeto de Hidrogênio/uso terapêutico , Neointima/patologia , Neointima/prevenção & controle , Enxerto Vascular/efeitos adversos , Remodelação Vascular , Anastomose Cirúrgica , Animais , Artéria Carótida Primitiva/cirurgia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neointima/etiologia , Veias Cavas/transplanteRESUMO
Chronic kidney disease (CKD) induces the failure of arteriovenous fistulas (AVFs) and promotes the differentiation of vascular adventitial GLI1-positive mesenchymal stem cells (GMCs). However, the roles of GMCs in forming neointima in AVFs remain unknown. GMCs isolated from CKD mice showed increased potential capacity of differentiation into myofibroblast-like cells. Increased activation of expression of PDGFRA and hedgehog (HH) signaling were detected in adventitial cells of AVFs from patients with end-stage kidney disease and CKD mice. PDGFRA was translocated and accumulated in early endosome when sonic hedgehog was overexpressed. In endosome, PDGFRA-mediated activation of TGFB1/SMAD signaling promoted the differentiation of GMCs into myofibroblasts, extracellular matrix deposition, and vascular fibrosis. These responses resulted in neointima formation and AVF failure. KO of Pdgfra or inhibition of HH signaling in GMCs suppressed the differentiation of GMCs into myofibroblasts. In vivo, specific KO of Pdgfra inhibited GMC activation and vascular fibrosis, resulting in suppression of neointima formation and improvement of AVF patency despite CKD. Our findings could yield strategies for maintaining AVF functions.
Assuntos
Fístula Arteriovenosa/patologia , Células-Tronco Mesenquimais/patologia , Músculo Liso Vascular/patologia , Miofibroblastos/patologia , Neointima/patologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/fisiologia , Insuficiência Renal Crônica/complicações , Animais , Fístula Arteriovenosa/etiologia , Fístula Arteriovenosa/metabolismo , Diferenciação Celular , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Miofibroblastos/metabolismo , Neointima/etiologia , Neointima/metabolismoRESUMO
Intracoronary stenting is a common procedure in patients with coronary artery disease (CAD). Stent deployment stretches and denudes the endothelial layer, promoting a local inflammatory response, resulting in neointimal hyperplasia. Vitamin D deficiency associates with CAD. In this study, we examined the association of vitamin D status with high mobility group box 1 (HMGB1)-mediated pathways (HMGB1, receptor for advanced glycation end products [RAGE], and Toll-like receptor-2 and -4 [TLR2 and TLR4]) in neointimal hyperplasia in atherosclerotic swine following bare metal stenting. Yucatan microswine fed with a high-cholesterol diet were stratified to receive vitamin D-deficient (VD-DEF), vitamin D-sufficient (VD-SUF), and vitamin D-supplemented (VD-SUP) diet. After 6 months, PTCA (percutaneous transluminal balloon angioplasty) followed by bare metal stent implantation was performed in the left anterior descending (LAD) artery of each swine. Four months following coronary intervention, angiogram and optical coherence tomography (OCT) were performed and swine euthanized. Histology and immunohistochemistry were performed in excised LAD to evaluate the expression of HMGB1, RAGE, TLR2, and TLR4. OCT analysis revealed the greatest in-stent restenosis area in the LAD of VD-DEF compared to VD-SUF or VD-SUP swine. The protein expression of HMGB1, RAGE, TLR2, and TLR4 was significantly higher in the LAD of VD-DEF compared to VD-SUF or VD-SUP swine. Vitamin D deficiency was associated with both increased in-stent restenosis and increased HMGB1-mediated inflammation noted in coronary arteries following intravascular stenting. Inversely, vitamin D supplementation was associated with both a decrease in this inflammatory profile and in neointimal hyperplasia, warranting further investigation for vitamin D as a potential adjunct therapy following coronary intervention.
Assuntos
Doença da Artéria Coronariana/cirurgia , Proteína HMGB1/metabolismo , Hiperplasia/prevenção & controle , Neointima/prevenção & controle , Intervenção Coronária Percutânea/efeitos adversos , Stents/efeitos adversos , Vitamina D/administração & dosagem , Animais , Doença da Artéria Coronariana/patologia , Feminino , Proteína HMGB1/genética , Hiperplasia/etiologia , Hiperplasia/metabolismo , Hiperplasia/patologia , Masculino , Neointima/etiologia , Neointima/metabolismo , Neointima/patologia , Suínos , Vitaminas/administração & dosagemRESUMO
BACKGROUND: Although self-expanding drug-eluting stents (DES) have recently shown superior outcomes for superficial femoral artery (SFA) lesions, optimal sizing of DES diameter in SFA intervention is unclear.MethodsâandâResults:A total of 40 de novo SFA lesions were randomized 1:1 to receive self-expanding DES with either a 1-mm or 2-mm larger diameter than the reference vessel diameter. Follow-up optical coherence tomography (OCT) was scheduled 6 months after DES implantation to evaluate the vascular response to the stents. Volume index (VI) was defined as volume divided by stent length. The primary endpoint was neointimal VI at 6 months. Baseline reference vessel diameter was similar between the 1-mm larger diameter group and the 2-mm larger diameter group (5.0±0.8 mm vs. 4.7±0.9 mm, P=0.35). Stent diameter was 6.3±0.6 mm in the 1-mm larger group and 7.1±0.6 mm in the 2-mm larger group (P<0.0001), and stent to reference vessel diameter ratio (SV ratio) was 1.3±0.2 and 1.5±0.2 (P<0.0001), respectively. At 6-month, neointimal VI was greater in the 2-mm larger diameter group (5.5±1.5 mm2vs. 9.6±3.4 mm2, P<0.001). The correlation analysis revealed that degree of neointimal VI was positively correlated with SV ratio (r=0.43, P<0.01). CONCLUSIONS: Implantation of self-expanding DES with a considerably high SV ratio resulted in neointimal hyperplasia in SFA lesions.
Assuntos
Stents Farmacológicos/efeitos adversos , Procedimentos Endovasculares/efeitos adversos , Artéria Femoral/patologia , Neointima/etiologia , Paclitaxel/administração & dosagem , Doença Arterial Periférica/cirurgia , Stents Metálicos Autoexpansíveis/efeitos adversos , Idoso , Feminino , Artéria Femoral/diagnóstico por imagem , Seguimentos , Humanos , Hiperplasia/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Neointima/diagnóstico por imagem , Estudos Prospectivos , Desenho de Prótese , Tomografia de Coerência Óptica/métodos , Resultado do TratamentoRESUMO
BACKGROUND: In-stent neoatherosclerosis (NA) is a risk for future cardiovascular events through atherosclerotic progression in non-stented lesions. Using optical coherence tomography, this study assessed the efficacy of intensive therapy with 10 mg/day rosuvastatin plus 1,800 mg/day eicosapentaenoic acid (EPA) vs. standard 2.5 mg/day rosuvastatin therapy on native coronary plaques in patients with NA.MethodsâandâResults:This was a subgroup analysis of the randomized LINK-IT trial, which was designed to compare changes in the lipid index in NA between intensive and standard therapy for 12 months. In all, 42 patients with native coronary plaques and NA were assessed. Compared with standard therapy, intensive therapy resulted in greater decreases in serum low-density lipoprotein cholesterol concentrations and greater increases in serum 18-hydroxyeicosapentaenoic acid concentrations, with significantly greater decreases in the lipid index and macrophage grade in both NA (-24 vs. 217 [P<0.001] and -15 vs. 24 [P<0.001], respectively) and native coronary plaques (-112 vs. 29 [P<0.001] and -17 vs. 1 [P<0.001], respectively) following intensive therapy. Although there was a greater increase in the macrophage grade in NA than in native coronary plaques in the standard therapy group, in the intensive therapy group there were comparable reductions in macrophage grade between NA and native coronary plaques. CONCLUSIONS: Compared with standard therapy, intensive therapy prevented atherosclerotic progression more effectively in native coronary plaques in patients with NA.