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BACKGROUND: The willingness of interventional cardiologists to adopt innovation and implement changes in day-to-day practice has received limited study. METHODS: Online-based survey on learning and innovation: 38 questions were distributed via email list to interventional cardiologists. RESULTS: The survey was distributed to 8,110 e-mails and completed by 621 (7.7%, 91.8% men, 60% in the 35 to 54-year-old age group). Of the respondents who perform coronary interventions, 45% perform >100 cases of noncomplex percutaneous coronary interventions per year and of the respondents who perform structural interventions, 15% perform more than >100 transcatheter aortic valve replacements per year. Most respondents (86.7%) rate themselves as highly likely/likely to introduce recently approved equipment in everyday practice and 47.5% have tried a new coronary guidewire in the past 6 months. The most common reasons for reluctance to use new equipment were high cost (64%) and uncertainty about whether it provides additional benefits compared with existing equipment (48.5%). Radial access in STEMI cases is always used by 43.6% of the respondents and 55% always use radial access for coronary angiography. Of those who use femoral access, 32% always use ultrasound guidance and 91% have used a closure device in the last 6 months. Most respondents (80%) read journals to keep up with current practice and believe that the most effective way to learn is through attendance of workshops/short courses (77.5%). Most respondents (69%) are involved in research. CONCLUSION: Interventional cardiologists who participated in the survey are highly likely to adopt innovation in daily clinical practice.
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Cardiologistas , Intervenção Coronária Percutânea , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Artéria Radial , Inquéritos e Questionários , Resultado do TratamentoRESUMO
OBJECTIVES: To investigate the perceptions of interventional cardiologists (IC) regarding the frequency, impact, and management strategies of percutaneous coronary intervention (PCI) complications. BACKGROUND: The perceptions and management strategies of ICs of PCI complications have received limited study. METHODS: Online survey on PCI complications: 46 questions were distributed via email lists and Twitter to ICs. RESULTS: Of 11,663 contacts, 821 responded (7% response rate): 60% were from the United States and the median age was 46-50 years. Annual PCI case numbers were <100 (26%), 100-199 (37%), 200-299 (21%), and ≥300 (16%); 42% do not perform structural interventions, others reported performing <40 (30%), or >100 (11%) structural cases annually. On a scale of 0-10, participating ICs were highly concerned about potential complications with a median score of 7.2 (interquartile range: 5.0-8.7). The most feared complication was death (39%), followed by coronary perforation (26%) and stroke (9%). Covered stents were never deployed by 21%, and 32% deployed at least one during the past year; 79% have never used fat to seal perforations; 64% have never used coils for perforations. Complications were attributed to higher patient/angiographic complexity by 68% and seen as opportunities for improvement by 70%; 97% of participants were interested in learning more about the management of PCI complications. The most useful learning methods were meetings (66%), webinars (48%), YouTube (32%), and Twitter (29%). CONCLUSION: ICs who participated in the survey are highly concerned about complications. Following complication management algorithms and having access to more experienced operators might alleviate stress and optimize patient outcomes.
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Cardiologistas , Traumatismos Cardíacos , Intervenção Coronária Percutânea , Humanos , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Inquéritos e Questionários , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
RATIONALE: Neutrophils likely contribute to the thrombotic complications of human atheromata. In particular, neutrophil extracellular traps (NETs) could exacerbate local inflammation and amplify and propagate arterial intimal injury and thrombosis. PAD4 (peptidyl arginine deiminase 4) participates in NET formation, but an understanding of this enzyme's role in atherothrombosis remains scant. OBJECTIVE: This study tested the hypothesis that PAD4 and NETs influence experimental atherogenesis and in processes implicated in superficial erosion, a form of plaque complication we previously associated with NETs. METHODS AND RESULTS: Bone marrow chimeric Ldlr deficient mice reconstituted with either wild-type or PAD4-deficient cells underwent studies that assessed atheroma formation or procedures designed to probe mechanisms related to superficial erosion. PAD4 deficiency neither retarded fatty streak formation nor reduced plaque size or inflammation in bone marrow chimeric mice that consumed an atherogenic diet. In contrast, either a PAD4 deficiency in bone marrow-derived cells or administration of DNaseI to disrupt NETs decreased the extent of arterial intimal injury in mice with arterial lesions tailored to recapitulate characteristics of human atheroma complicated by erosion. CONCLUSIONS: These results indicate that PAD4 from bone marrow-derived cells and NETs do not influence chronic experimental atherogenesis, but participate causally in acute thrombotic complications of intimal lesions that recapitulate features of superficial erosion.
Assuntos
Armadilhas Extracelulares/fisiologia , Hidrolases/fisiologia , Placa Aterosclerótica/etiologia , Trombose/etiologia , Animais , Transplante de Medula Óssea , Doenças das Artérias Carótidas/etiologia , Doenças das Artérias Carótidas/patologia , Morte Celular , Desoxirribonuclease I/farmacologia , Armadilhas Extracelulares/efeitos dos fármacos , Humanos , Hidrolases/deficiência , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/fisiologia , Osteomielite/etiologia , Placa Aterosclerótica/patologia , Proteína-Arginina Desiminase do Tipo 4 , Trombose/prevenção & controle , Túnica Íntima/lesõesRESUMO
RATIONALE: Superficial erosion currently causes up to a third of acute coronary syndromes; yet, we lack understanding of its mechanisms. Thrombi because of superficial intimal erosion characteristically complicate matrix-rich atheromata in regions of flow perturbation. OBJECTIVE: This study tested in vivo the involvement of disturbed flow and of neutrophils, hyaluronan, and Toll-like receptor 2 ligation in superficial intimal injury, a process implicated in superficial erosion. METHODS AND RESULTS: In mouse carotid arteries with established intimal lesions tailored to resemble the substrate of human eroded plaques, acute flow perturbation promoted downstream endothelial cell activation, neutrophil accumulation, endothelial cell death and desquamation, and mural thrombosis. Neutrophil loss-of-function limited these findings. Toll-like receptor 2 agonism activated luminal endothelial cells, and deficiency of this innate immune receptor decreased intimal neutrophil adherence in regions of local flow disturbance, reducing endothelial cell injury and local thrombosis (P<0.05). CONCLUSIONS: These results implicate flow disturbance, neutrophils, and Toll-like receptor 2 signaling as mechanisms that contribute to superficial erosion, a cause of acute coronary syndrome of likely growing importance in the statin era.
Assuntos
Velocidade do Fluxo Sanguíneo/fisiologia , Endotélio Vascular/metabolismo , Infiltração de Neutrófilos/fisiologia , Receptor 2 Toll-Like/deficiência , Animais , Transplante de Medula Óssea/métodos , Estenose das Carótidas/metabolismo , Estenose das Carótidas/patologia , Células Cultivadas , Endotélio Vascular/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
OBJETIVES: The main objective of the present randomized pilot study was to explore the effects of upstream prasugrel or ticagrelor or clopidogrel for patients with ST-segment-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). BACKGROUND: Administration of clopidogrel "as soon as possible" has been advocated for STEMI. Pretreatment with prasugrel and ticagrelor may improve reperfusion. Currently, the angiographic effects of upstream administration of these agents are poorly understood. METHODS: A total of 132 patients with STEMI within the first 12 hr of chest pain referred to primary angioplasty were randomized to upstream clopidogrel (600 mg), prasugrel (60 mg), or ticagrelor (180 mg) while still in the emergency room. All patients underwent protocol-mandated thrombus aspiration. RESULTS: Macroscopic thrombus material was retrieved in 79.5% of the clopidogrel group, 65.9% of the prasugrel group, and 54.3% of the ticagrelor group (P = 0.041). At baseline angiography, large thrombus burden was 97.7% vs. 87.8% vs. 80.4% in the clopidogrel, prasugrel, and ticagrelor groups, respectively (P = 0.036). Also, at baseline, 97.7% presented with an occluded target vessel in the clopidogrel group, 87.8% in the prasugrel group and 78.3% in the ticagrelor group (P = 0.019). At the end of the procedure, the percentages of patients with combined TIMI grade III flow and myocardial blush grade III were 52.3% for clopidogrel, 80.5% for prasugrel, and 67.4% for ticagrelor (P = 0.022). CONCLUSIONS: In patients with STEMI undergoing primary PCI within 12 hr, upstream clopidogrel, prasugrel or ticagrelor have varying angiographic findings, with a trend toward better results for the latter two agents. © 2015 Wiley Periodicals, Inc.
Assuntos
Adenosina/análogos & derivados , Angioplastia Coronária com Balão , Angiografia Coronária , Inibidores da Agregação Plaquetária/administração & dosagem , Cloridrato de Prasugrel/administração & dosagem , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Ticlopidina/análogos & derivados , Adenosina/administração & dosagem , Adenosina/efeitos adversos , Idoso , Angioplastia Coronária com Balão/efeitos adversos , Brasil , Clopidogrel , Esquema de Medicação , Serviços Médicos de Emergência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Inibidores da Agregação Plaquetária/efeitos adversos , Cloridrato de Prasugrel/efeitos adversos , Valor Preditivo dos Testes , Estudos Prospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Trombectomia , Ticagrelor , Ticlopidina/administração & dosagem , Ticlopidina/efeitos adversos , Fatores de Tempo , Tempo para o Tratamento , Resultado do TratamentoRESUMO
T cell subset-specific migration to inflammatory sites is tightly regulated and involves interaction of the T cells with the endothelium. Th17 cells often appear at different inflammatory sites than Th1 cells, or both subsets appear at the same sites but at different times. Differences in T cell subset adhesion to endothelium may contribute to subset-specific migratory behavior, but this possibility has not been well studied. We examined the adhesion of mouse Th17 cells to endothelial adhesion molecules and endothelium under flow in vitro and to microvessels in vivo and we characterized their migratory phenotype by flow cytometry and quantitative RT-PCR. More Th17 than Th1 cells interacted with E-selectin. Fewer Th17 than Th1 cells bound to TNF-α-activated E-selectin-deficient endothelial cells, and intravital microscopy studies demonstrated that Th17 cells engage in more rolling interactions with TNF-α-treated microvessels than Th1 cells in wild-type mice but not in E-selectin-deficient mice. Th17 adhesion to ICAM-1 was dependent on integrin activation by CCL20, the ligand for CCR6, which is highly expressed by Th17 cells. In an air pouch model of inflammation, CCL20 triggered recruitment of Th17 but not Th1 cells. These data provide evidence that E-selectin- and ICAM-1-dependent adhesion of Th17 and Th1 cells with endothelium are quantitatively different.
Assuntos
Adesão Celular/imunologia , Endotélio Vascular/imunologia , Células Th1/fisiologia , Animais , Quimiocina CCL20/metabolismo , Selectina E/imunologia , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiologia , Molécula 1 de Adesão Intercelular/imunologia , Camundongos , Células Th17RESUMO
At sites of inflammation, endothelial adhesion molecules bind leukocytes and transmit signals required for transendothelial migration (TEM). We previously reported that adhesive interactions between endothelial cell CD47 and leukocyte signal regulatory protein γ (SIRPγ) regulate human T cell TEM. The role of endothelial CD47 in T cell TEM in vivo, however, has not been explored. In this study, CD47â»/â» mice showed reduced recruitment of blood T cells as well as neutrophils and monocytes in a dermal air pouch model of TNF-α-induced inflammation. Reconstitution of CD47â»/â» mice with wild-type bone marrow cells did not restore leukocyte recruitment to the air pouch, indicating a role for endothelial CD47. The defect in leukocyte TEM in the CD47â»/â» endothelium was corroborated by intravital microscopy of inflamed cremaster muscle microcirculation in bone marrow chimera mice. In an in vitro human system, CD47 on both HUVEC and T cells was required for TEM. Although previous studies showed CD47-dependent signaling required G(αi)-coupled pathways, this was not the case for endothelial CD47 because pertussis toxin, which inactivates G(αi), had no inhibitory effect, whereas G(αi) was required by the T cell for TEM. We next investigated the endothelial CD47-dependent signaling events that accompany leukocyte TEM. Ab-induced cross-linking of CD47 revealed robust actin cytoskeleton reorganization and Src- and Pyk-2-kinase dependent tyrosine phosphorylation of the vascular endothelial-cadherin cytoplasmic tail. This signaling was pertussis toxin insensitive, suggesting that endothelial CD47 signaling is independent of G(αi). These findings suggest that engagement of endothelial CD47 by its ligands triggers outside-in signals in endothelium that facilitate leukocyte TEM.
Assuntos
Antígeno CD47/fisiologia , Caderinas/sangue , Quimiotaxia de Leucócito/imunologia , Endotélio Vascular/metabolismo , Inflamação/imunologia , Inflamação/patologia , Subpopulações de Linfócitos T/imunologia , Tirosina/sangue , Animais , Antígeno CD47/genética , Antígeno CD47/metabolismo , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/sangue , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação/imunologia , Proteínas Recombinantes/toxicidade , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Fator de Necrose Tumoral alfa/toxicidadeRESUMO
IL-17A (IL-17) is the signature cytokine produced by Th17 cells and has been implicated in host defense against infection and the pathophysiology of autoimmunity and cardiovascular disease. Little is known, however, about the influence of IL-17 on endothelial activation and leukocyte influx to sites of inflammation. We hypothesized that IL-17 would induce a distinct pattern of endothelial activation and leukocyte recruitment when compared with the Th1 cytokine IFN-γ. We found that IL-17 alone had minimal activating effects on cultured endothelium, whereas the combination of TNF-α and IL-17 produced a synergistic increase in the expression of both P-selectin and E-selectin. Using intravital microscopy of the mouse cremaster muscle, we found that TNF-α and IL-17 also led to a synergistic increase in E-selectin-dependent leukocyte rolling on microvascular endothelium in vivo. In addition, TNF-α and IL-17 enhanced endothelial expression of the neutrophilic chemokines CXCL1, CXCL2, and CXCL5 and led to a functional increase in leukocyte transmigration in vivo and CXCR2-dependent neutrophil but not T cell transmigration in a parallel-plate flow chamber system. By contrast, endothelial activation with TNF-α and IFN-γ preferentially induced the expression of the integrin ligands ICAM-1 and VCAM-1, as well as the T cell chemokines CXCL9, CXCL10, and CCL5. These effects were further associated with a functional increase in T cell but not neutrophil transmigration under laminar shear flow. Overall, these data show that IL-17 and TNF-α act in a synergistic manner to induce a distinct pattern of endothelial activation that sustains and enhances neutrophil influx to sites of inflammation.
Assuntos
Células Endoteliais/metabolismo , Inflamação/metabolismo , Interleucina-17/metabolismo , Infiltração de Neutrófilos/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Quimiocinas/biossíntese , Células Endoteliais/imunologia , Citometria de Fluxo , Inflamação/imunologia , Interleucina-17/imunologia , Migração e Rolagem de Leucócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/imunologiaRESUMO
The prevalence of calcification in obstructive coronary artery disease is on the rise. Percutaneous coronary intervention of these calcified lesions is associated with increased short-term and long-term risks. To optimize percutaneous coronary intervention results, there is an expanding array of treatment modalities geared toward calcium modification prior to stent implantation. The Society for Cardiovascular Angiography and Interventions, herein, puts forth an expert consensus document regarding methods to identify types of calcified coronary lesions, a central algorithm to help guide use of the various calcium modification strategies, tips for when using each treatment modality, and a look at future studies and trials for treating this challenging lesion subset.
RESUMO
The ability of regulatory T cells (Treg) to traffic to sites of inflammation supports their role in controlling immune responses. This feature supports the idea that adoptive transfer of in vitro expanded human Treg could be used for treatment of immune/inflammatory diseases. However, the migratory behavior of Treg, as well as their direct influence at the site of inflammation, remains poorly understood. To explore the possibility that Treg may have direct anti-inflammatory influences on tissues, independent of their well-established suppressive effects on lymphocytes, we studied the adhesive interactions between mouse Treg and endothelial cells, as well as their influence on endothelial function during acute inflammation. We show that Foxp3(+) adaptive/inducible Treg (iTreg), but not naturally occurring Treg, efficiently interact with endothelial selectins and transmigrate through endothelial monolayers in vitro. In response to activation by endothelial Ag presentation or immobilized anti-CD3ε, Foxp3(+) iTreg suppressed TNF-α- and IL-1ß-mediated endothelial selectin expression and adhesiveness to effector T cells. This suppression was contact independent, rapid acting, and mediated by TGF-ß-induced activin receptor-like kinase 5 signaling in endothelial cells. In addition, Foxp3(+) iTreg adhered to inflamed endothelium in vivo, and their secretion products blocked acute inflammation in a model of peritonitis. These data support the concept that Foxp3(+) iTreg help to regulate inflammation independently of their influence on effector T cells by direct suppression of endothelial activation and leukocyte recruitment.
Assuntos
Quimiotaxia de Leucócito/imunologia , Endotélio Vascular/imunologia , Inflamação/imunologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Animais , Adesão Celular/imunologia , Separação Celular , Endotélio Vascular/metabolismo , Citometria de Fluxo , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Técnicas de Introdução de Genes , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/metabolismoRESUMO
Background: Long-term outcomes after percutaneous coronary intervention (PCI) for in-stent restenosis (ISR) are poor, yet limited granular procedural data exist evaluating lesion assessment, vessel treatment, and acute procedural outcomes. Methods: The LightLab Initiative was a multicenter, prospective, observational study with contemporaneous procedural data collection during PCI procedures. Data were collected during PCIs performed by 48 interventional cardiologists at 17 US hospitals (2019-2021). Optical coherence tomography (OCT) was performed pre-PCI for lesion assessment and post-PCI for stent optimization, and results were compared between ISR and de novo lesion PCI. Results: In total, 2592 OCT-guided PCIs involving 2944 lesions were included, of which 458 procedures (17.7%) were ISR PCI. Compared with de novo lesion PCI, ISR lesions were more commonly type C (64.8% vs 52.9%) and performed via femoral artery access (46.4% vs 37.7%). Use of OCT changed operator assessment and treatment decisions more frequently in ISR PCI (94.2% vs 85.2%; P = .002). Scoring balloons (21.8% vs 2.5%), cutting balloons (16.4% vs 3.4%), and atherectomy (26.3% vs 9.9%) were used more commonly in ISR PCI (all P < .0001), and ISR PCI procedures were longer (62 vs 51 min). Moreover, the final achieved minimum stent area and percent expansion (4.4 vs 5.1 mm2 and 80% vs 83%, respectively; both P < .0001) were lower in ISR PCI. Conclusions: In this real-world cohort of patients who underwent OCT-guided PCI, ISR procedures were longer and final minimum stent area and percent expansion were lower despite greater use of advanced lesion modification. OCT frequently altered physician decision making, emphasizing its utility in potentially reducing recurrent stent failure in this high-risk population.
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True trifurcation disease in left main coronary artery is an infrequent but highly complex substrate for percutaneous coronary intervention. Evidence for optimal stenting strategy for such anatomy is lacking. We describe a novel three-stent strategy using a combination of double-kissing crush (DK crush) and Culotte techniques in three patients. This approach, based on established bifurcation stenting techniques, appeared reproducible in all three cases.
Assuntos
Doença da Artéria Coronariana , Intervenção Coronária Percutânea , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/terapia , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/métodos , Stents , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) can improve patient symptoms, but it remains controversial whether it impacts subsequent clinical outcomes. METHODS: In this systematic review and meta-analysis, we queried PubMed, ScienceDirect, Cochrane Library, Web of Science, and Embase databases (last search: September 15, 2021). We investigated the impact of CTO-PCI on clinical events including all-cause mortality, cardiovascular death, myocardial infarction (MI), major adverse cardiovascular event (MACE), stroke, subsequent coronary artery bypass surgery, target-vessel revascularization, and heart failure hospitalizations. Pooled analysis was performed using a random-effects model. RESULTS: A total of 58 publications with 54,540 patients were included in this analysis, of which 33 were observational studies of successful vs failed CTO-PCI, 19 were observational studies of CTO-PCI vs no CTO-PCI, and 6 were randomized controlled trials (RCTs). In observational studies, but not RCTs, CTO-PCI was associated with better clinical outcomes. Odds ratios (ORs) and 95% confidence intervals (CIs) for all-cause mortality, MACE, and MI were 0.52 (95% CI, 0.42-0.64), 0.46 (95% CI, 0.37-0.58), 0.66 (95% CI, 0.50-0.86), respectively for successful vs failed CTO-PCI studies; 0.38 (95% CI, 0.31-0.45), 0.57 (95% CI, 0.42-0.78), 0.65 (95% CI, 0.42-0.99), respectively, for observational studies of CTO-PCI vs no CTO-PCI; 0.72 (95% CI, 0.39-1.32), 0.69 (95% CI, 0.38-1.25), and 1.04 (95% CI, 0.46-2.37), respectively for RCTs. CONCLUSIONS: CTO-PCI is associated with better subsequent clinical outcomes in observational studies but not in RCTs. Appropriately powered RCTs are needed to conclusively determine the impact of CTO-PCI on clinical outcomes.
Assuntos
Oclusão Coronária , Infarto do Miocárdio , Intervenção Coronária Percutânea , Humanos , Oclusão Coronária/cirurgia , Resultado do Tratamento , Intervenção Coronária Percutânea/efeitos adversos , Infarto do Miocárdio/etiologia , Razão de Chances , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Observacionais como AssuntoRESUMO
BACKGROUND AND AIMS: We aimed to characterize the spatial proximity of plaque destabilizing features local endothelial shear stress (ESS), minimal luminal area (MLA), plaque burden (PB), and near-infrared spectroscopy (NIRS) lipid signal in high- vs. low-risk plaques. METHODS: Coronary arteries imaged with angiography and NIRS-intravascular ultrasound (IVUS) underwent 3D reconstruction and computational fluid dynamics calculations of local ESS. ESS, PB, MLA, and lipid core burden index (LCBI), for each 3-mm arterial segment were obtained in arteries with large lipid-rich plaque (LRP) vs. arteries with smaller LRP. The locations of the MLA, minimum ESS (minESS), maximum ESS (maxESS), maximum PB (maxPB), and maximum LCBI in a 4-mm segment (maxLCBI4mm) were determined along the length of each plaque. RESULTS: The spatial distributions of minESS, maxESS, maxPB, and maxLCBI4mm, in reference to the MLA, were significantly heterogeneous within and between each variable. The location of maxLCBI4mm was spatially discordant from sites of the MLA (p<0.0001), minESS (p = 0.003), and maxESS (p = 0.003) in arteries with large LRP (maxLCBI4mm ≥ 400) and non-large LRP. Large LRP arteries had higher maxESS (9.31 ± 4.78 vs. 6.32 ± 5.54 Pa; p = 0.023), lower minESS (0.41 ± 0.16 vs. 0.61 ± 0.26 Pa; p = 0.007), smaller MLA (3.54 ± 1.22 vs. 5.14 ± 2.65 mm2; p = 0.002), and larger maxPB (70.64 ± 9.95% vs. 56.70 ± 13.34%, p<0.001) compared with non-large LRP arteries. CONCLUSIONS: There is significant spatial heterogeneity of destabilizing plaque features along the course of both large and non-large LRPs. Large LRPs exhibit significantly more abnormal destabilizing plaque features than non-large LRPs. Prospective, longitudinal studies are required to determine which patterns of heterogeneous destabilizing features act synergistically to cause plaque destabilization.
Assuntos
Doença da Artéria Coronariana , Placa Aterosclerótica , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Hemodinâmica , Humanos , Estudos Prospectivos , Ultrassonografia de IntervençãoRESUMO
AIMS: Recent evidence suggests that 'vulnerable plaques', which have received intense attention as underlying mechanism of acute coronary syndromes over the decades, actually rarely rupture and cause clinical events. Superficial plaque erosion has emerged as a growing cause of residual thrombotic complications of atherosclerosis in an era of increased preventive measures including lipid lowering, antihypertensive therapy, and smoking cessation. The mechanisms of plaque erosion remain poorly understood, and we currently lack validated effective diagnostics or therapeutics for superficial erosion. Eroded plaques have a rich extracellular matrix, an intact fibrous cap, sparse lipid, and few mononuclear cells, but do harbour neutrophil extracellular traps (NETs). We recently reported that NETs amplify and propagate the endothelial damage at the site of arterial lesions that recapitulate superficial erosion in mice. We showed that genetic loss of protein arginine deiminase (PAD)-4 function inhibited NETosis and preserved endothelial integrity. The current study used systemic administration of targeted nanoparticles to deliver an agent that limits NETs formation to probe mechanisms of and demonstrate a novel therapeutic approach to plaque erosion that limits endothelial damage. METHODS AND RESULTS: We developed Collagen IV-targeted nanoparticles (Col IV NP) to deliver PAD4 inhibitors selectively to regions of endothelial cell sloughing and collagen IV-rich basement membrane exposure. We assessed the binding capability of the targeting ligand in vitro and evaluated Col IV NP targeting to areas of denuded endothelium in vivo in a mouse preparation that recapitulates features of superficial erosion. Delivery of the PAD4 inhibitor GSK484 reduced NET accumulation at sites of intimal injury and preserved endothelial continuity. CONCLUSIONS: NPs directed to Col IV show selective uptake and delivery of their payload to experimentally eroded regions, illustrating their translational potential. Our results further support the role of PAD4 and NETs in superficial erosion.
Assuntos
Aterosclerose/tratamento farmacológico , Colágeno Tipo IV/metabolismo , Portadores de Fármacos , Células Endoteliais/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Armadilhas Extracelulares/metabolismo , Nanopartículas , Proteína-Arginina Desiminase do Tipo 4/antagonistas & inibidores , Animais , Aterosclerose/enzimologia , Aterosclerose/patologia , Membrana Basal/metabolismo , Técnicas de Cultura de Células em Três Dimensões , Células Cultivadas , Colágeno Tipo IV/química , Modelos Animais de Doenças , Composição de Medicamentos , Liberação Controlada de Fármacos , Células Endoteliais/enzimologia , Células Endoteliais/patologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Masculino , Camundongos Knockout para ApoE , Nanotecnologia , Placa Aterosclerótica , Ligação Proteica , Proteína-Arginina Desiminase do Tipo 4/metabolismo , Propriedades de Superfície , Distribuição TecidualRESUMO
Down-regulation of the forkhead transcription factor Foxp1 by integrin engagement controls monocyte differentiation in vitro. To determine whether Foxp1 plays a critical role in monocyte differentiation and macrophage functions in vivo, we generated transgenic mice (macFoxp1tg) overexpressing human FOXP1 in monocyte/macrophage lineage cells using the CD68 promoter. Circulating blood monocytes from macFoxp1tg mice have reduced expression of the receptor for macrophage colony-stimulating factor (c-Fms/M-CSFR), impaired migratory capacity, and diminished accumulation as splenic macrophages. Macrophage functions, including cytokine production, phagocytosis, and respiratory burst were globally impaired in macFoxp1tg compared with wild-type cells. Osteoclastogenesis and bone resorption activity were also attenuated in macFoxp1tg mice. In models of chemical and bacterial peritonitis, macFoxp1tg mice exhibited reduced macrophage accumulation, bacterial clearance, and survival. Enforced overexpression of c-Fms/M-CSFR reversed the cytokine production and phagocytosis defects in macFoxp1tg macrophages, indicating that repression of c-fms/M-CSFR is likely the dominant mechanism responsible for Foxp1 action in monocyte differentiation and macrophage function. Taken together, these observations identify down-regulation of Foxp1 as critical for monocyte differentiation and macrophage functions in vivo.
Assuntos
Diferenciação Celular/genética , Fatores de Transcrição Forkhead/genética , Macrófagos/fisiologia , Monócitos/fisiologia , Proteínas Repressoras/genética , Animais , Contagem de Células , Células Cultivadas , Citocinas/metabolismo , Regulação para Baixo/fisiologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/fisiologia , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/genética , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monócitos/citologia , Monócitos/metabolismo , Especificidade de Órgãos/genética , Gravidez , Proteínas Repressoras/metabolismo , Proteínas Repressoras/fisiologiaAssuntos
Dor no Peito/diagnóstico , Vasos Coronários/patologia , Infarto do Miocárdio/diagnóstico , Tomografia de Coerência Óptica/métodos , Dor no Peito/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Tomografia de Coerência Óptica/tendênciasRESUMO
BACKGROUND: Subjects undergoing coronary stenting with complex lesion anatomy may experience different risks and benefits with prolonged dual antiplatelet therapy. OBJECTIVES: The authors assessed the effect of 30 months versus 12 months of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) based on the presence or absence of anatomically-complex target lesions. METHODS: In the DAPT Study, combined myocardial infarction (MI) or stent thrombosis and moderate/severe bleeding were assessed in enrolled (n = 25,416) and randomized (n = 11,554) subjects. Complex lesions had any of the following characteristics: unprotected left main, >2 lesions/vessel, length ≥30 mm, bifurcation with side branch ≥2.5 mm, vein bypass graft, or thrombus-containing lesion. Events were evaluated according to increasing number of complexity characteristics and compared according to DAPT score. RESULTS: Enrolled subjects with more complex target lesions had higher rates of MI or stent thrombosis in the first 12 months after PCI (3.9% vs. 2.4%; p < 0.001). Among those who were event-free at 12 months, rates of MI or stent thrombosis between 12 and 30 months were similar between those with versus without complex anatomy (3.5% vs. 2.9%; p = 0.07). Reduction of MI or stent thrombosis with continued thienopyridine beyond 12 months versus placebo was similar for subjects with (2.5% vs. 4.5%; hazard ratio: 0.55; 95% confidence interval: 0.38 to 0.79; p = 0.001) and without (2.0% vs. 3.8%; hazard ratio: 0.52; 95% confidence interval: 0.39 to 0.69; p < 0.001) anatomic complexity (pinteraction = 0.81), as was increase in moderate/severe bleeding (pinteraction = 0.44). Among subjects with anatomic complexity, those with DAPT scores ≥2 randomized to continued thienopyridine had greater reductions in MI or stent thrombosis (3.0% vs. 6.1%; p < 0.001) compared with subjects with scores <2 (1.7% vs. 2.3%; p = 0.42; p value comparing risk differences = 0.03). CONCLUSIONS: Complex target-lesion anatomy is associated with increased ischemic events, particularly within the first year after PCI. Among those without events in the first 12 months, the benefits of extending DAPT were similar in subjects with and without complex lesions. A high DAPT score identified those experiencing the most benefit from extended treatment among patients with and without complex anatomy. (The Dual Antiplatelet Therapy Study [DAPT Study]; NCT00977938).
Assuntos
Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/tratamento farmacológico , Internacionalidade , Intervenção Coronária Percutânea/tendências , Inibidores da Agregação Plaquetária/administração & dosagem , Idoso , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Clopidogrel , Doença da Artéria Coronariana/cirurgia , Método Duplo-Cego , Esquema de Medicação , Stents Farmacológicos , Feminino , Seguimentos , Hemorragia/induzido quimicamente , Hemorragia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/etiologia , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Ticlopidina/administração & dosagem , Ticlopidina/efeitos adversos , Ticlopidina/análogos & derivados , Resultado do TratamentoRESUMO
In-stent restenosis (ISR) remains a concern even in the drug-eluting stent (DES) era and carries a high risk of recurrence. Brachytherapy is being used as an alternative treatment for resistant ISR, yet the safety and efficacy of this approach has not been well studied. We analyzed the outcomes of 101 patients who underwent coronary brachytherapy for resistant DES ISR. Baseline demographic, clinical, procedural, and outcome data were collected by phone and from electronic records. Comorbidities and overt cardiovascular disease were highly prevalent. Median previous stent layers were 2 with a maximum of 5 layers. Procedural angiographic success rate was 97% and median time to discharge was 1 day after brachytherapy. The primary outcome of target vessel revascularization was 24% at 1 year, 32% at 2 years, and 42% at 3 years. The rate of nonfatal myocardial infarction was 0% at 1 year, 3.5% at 2 years, and 6% at 3 years. The rate of all-cause mortality was 8.5% at 1 year, 12% at 2 years, and 16% at 3 years. We observed only 1 case of late stent thrombosis. After multivariable adjustment, female gender (hazard ratio 2.37, 95% confidence interval 1.02 to 5.52, p = 0.04) and diffuse ISR pattern (hazard ratio 2.95, 95% confidence interval 1.21 to 7.17, p = 0.01) were independently associated with the primary outcome. In conclusion, brachytherapy is feasible for the treatment of resistant DES ISR and is associated with high immediate procedural success and reasonable efficacy in a complex patient population. This approach might be used as an alternative for these patients.