RESUMEN
As the important factors in coronary artery thrombosis, endothelial injury and M1 macrophage polarization are closely related to the expression of miR-34a-5p. Exosomes in plasma are mainly derived from platelets and play an important role in thrombosis. Based on these facts, this study was conducted to investigate the acting mechanism of platelet-derived exosomes (PLT-exo) in the effects of endothelial injury and M1 macrophage polarization on coronary artery thrombosis. Firstly, rats were divided into the sham-operated group and the coronary microembolization (CME) group, and their plasma-derived exosomes were extracted to detect the expression of miR-34a-5p. Next, the PLT-exo were extracted from healthy volunteers and then co-cultured with ox-LDL-induced endothelial cells and LPS-induced macrophages, respectively. Subsequently, the expression of IL-1ß, IL-6, TNF-α, and ICAM-1 in endothelial cells was measured, and the level of markers related to M1 macrophage polarization and Sirt1/NF-κB pathway was detected. Finally, the above indicators were examined again after PLT-exo combined with miR-34a-5p mimic were co-cultured with endothelial cells and macrophages, respectively. The results demonstrated that the expression of miR-34a-5p in the CME group was up-regulated compared with the sham-operated group. In cell experiments, PLT-exo modulated the Sirt1/NF-κB pathway by inhibiting the expression of intracellular miR-34a-5p and down-regulated the expression of IL-1ß, IL-6, TNF-α, and ICAM-1 in endothelial cells and M1 macrophage polarization. After the transfection with miR-34a-5p mimic, endothelial cell inflammatory injury and M1 macrophage polarization increased to varying degrees. In conclusion, PLT-exo can alleviate coronary artery thrombosis by reducing endothelial cell inflammation and M1 macrophage polarization via inhibiting miR-34a-5p expression. In contrast, miR-34a-5p overexpression in PLT-exo may exacerbate these pathological injuries in coronary artery thrombosis.
Asunto(s)
Plaquetas , Células Endoteliales , Exosomas , Inflamación , Macrófagos , MicroARNs , MicroARNs/genética , MicroARNs/metabolismo , Exosomas/metabolismo , Animales , Macrófagos/metabolismo , Humanos , Plaquetas/metabolismo , Ratas , Inflamación/metabolismo , Inflamación/genética , Inflamación/patología , Masculino , Células Endoteliales/metabolismo , Trombosis Coronaria/metabolismo , Trombosis Coronaria/genética , Trombosis Coronaria/patología , Técnicas de Cocultivo , Ratas Sprague-DawleyRESUMEN
We describe the internal structure, spatial organization and dynamic formation of coronary artery thrombi from ST-segment elevation myocardial infarction patients. Scanning electron microscopy (SEM) revealed significant differences among four groups of patients (<2 hours; 2-6 hours; 6-12 hours, and >12 hours) related to the time of ischemia. Coronary artery thrombi from patients presenting less than 2 hours after the infarction were almost entirely composed of platelets, with small amounts of fibrin and red blood cells. In contrast, thrombi from late presenters (>12 hours) consisted of mainly platelets at the distal end, where clotting was initiated, with almost no platelets at the proximal end, while the red blood cell content went from low at the initiating end to more than 90% at the proximal end. Furthermore, fibrin was present mainly on the outside of the thrombi and older thrombi contained thicker fibers. The red blood cells in late thrombi were compressed to a close-packed, tessellated array of polyhedral structures, called polyhedrocytes. Moreover, there was redistribution from the originally homogeneous composition to fibrin and platelets to the outside, with polyhedrocytes on the interior. The presence of polyhedrocytes and the redistribution of components are signs of in vivo clot contraction (or retraction). These results suggest why later thrombi are resistant to fibrinolytic agents and other treatment modalities, since the close-packed polyhedrocytes form a nearly impermeable seal. Furthermore, it is of particular clinical significance that these findings suggest specific disparate therapies that will be most effective at different stages of thrombus development.
Asunto(s)
Plaquetas/patología , Trombosis Coronaria , Eritrocitos/patología , Fibrina/análisis , Fibrinolíticos , Infarto del Miocardio con Elevación del ST , Coagulación Sanguínea/efectos de los fármacos , Coagulación Sanguínea/fisiología , Trombosis Coronaria/diagnóstico por imagen , Trombosis Coronaria/tratamiento farmacológico , Trombosis Coronaria/metabolismo , Trombosis Coronaria/patología , Resistencia a Medicamentos/fisiología , Femenino , Fibrinolíticos/administración & dosificación , Fibrinolíticos/efectos adversos , Humanos , Masculino , Microscopía Electrónica de Rastreo/métodos , Persona de Mediana Edad , Infarto del Miocardio con Elevación del ST/etiología , Infarto del Miocardio con Elevación del ST/terapia , Trombectomía/métodos , Factores de Tiempo , Tiempo de TratamientoRESUMEN
While the advent of drug-eluting stents has been clinically effective in substantially reducing the rates of major stent-related adverse events compared with bare metal stents, vascular biological problems such as neointimal hyperplasia, delayed re-endothelialization, late stent thrombosis are not eliminated and, increasingly, neoatherosclerosis is the underlying mechanism for very late stent failure. Further understanding regarding the mechanisms underlying the biological responses to stent deployment is therefore required so that new and improved therapies can be developed. This review will discuss the accumulating evidence that the chemokines, small inflammatory proteins, play a role in each key biological process of stent biocompatibility. It will address the chemokine system in its specialized roles in regulating the multiple facets of vascular biocompatibility including neointimal hyperplasia, endothelial progenitor cell (EPC) mobilization and re-endothelialization after vascular injury, platelet activation and thrombosis, as well as neoatherosclerosis. The evidence in this review suggests that chemokine-targeting strategies may be effective in controlling the pathobiological processes that lead to stent failure. Preclinical studies provide evidence that inhibition of specific chemokines and/or broad-spectrum inhibition of the CC-chemokine class prevents neointimal hyperplasia, reduces thrombosis and suppresses the development of neoatherosclerosis. In contrast, however, to these apparent deleterious effects of chemokines on stent biocompatibility, the CXC chemokine, CXCL12, is essential for the mobilization and recruitment of EPCs that make important contributions to re-endothelialization post-stent deployment. This suggests that future chemokine inhibition strategies would need to be correctly targeted so that all key stent biocompatibility areas could be addressed, without compromising important adaptive biological responses.
Asunto(s)
Materiales Biocompatibles , Quimiocinas/metabolismo , Enfermedad de la Arteria Coronaria/terapia , Vasos Coronarios/metabolismo , Intervención Coronaria Percutánea/instrumentación , Stents , Animales , Quimiocinas/inmunología , Enfermedad de la Arteria Coronaria/inmunología , Enfermedad de la Arteria Coronaria/metabolismo , Enfermedad de la Arteria Coronaria/patología , Reestenosis Coronaria/inmunología , Reestenosis Coronaria/metabolismo , Reestenosis Coronaria/patología , Trombosis Coronaria/inmunología , Trombosis Coronaria/metabolismo , Trombosis Coronaria/patología , Vasos Coronarios/inmunología , Vasos Coronarios/patología , Stents Liberadores de Fármacos , Humanos , Hiperplasia , Neointima , Intervención Coronaria Percutánea/efectos adversos , Diseño de Prótesis , Transducción de Señal , Resultado del TratamientoRESUMEN
As the degree of luminal narrowing increases, shear stress increases, and high shear stress is known to activate platelets. However, the relationship between the degree of luminal narrowing and the composition of thrombus in patients with plaque erosion has not been studied. A total of 148 patients with plaque erosion and thrombus detected by optical coherence tomography were divided into tertiles based on the minimum lumen area (MLA) at the culprit lesion. Thrombus was categorized as platelet-rich or fibrin-rich. Among 148 patients, 50 (34%) were in the mild stenosis group, 49 (33%) were in the moderate stenosis group, and 49 (33%) were in the severe stenosis group. The composition of thrombus was significantly different among the 3 groups (prevalence of platelet-rich thrombus was 60% in the mild stenosis group; 78% in the moderate stenosis group; and 84% in the severe stenosis group; P = 0.021). The pattern of fibrin-rich thrombus showed the opposite: 40%, 22%, and 16%, respectively. In the multivariate analysis, current smoking was independently associated with fibrin-rich thrombus (odds ratio [OR] 2.364 [95% CI 1.004-5.567], P = 0.049). This study demonstrated that platelet-rich thrombus was the predominant type of thrombus in plaque erosion. The prevalence of fibrin-rich thrombus was highest in the mild stenosis group.
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Plaquetas/patología , Trombosis Coronaria/patología , Placa Aterosclerótica/patología , Adulto , Anciano , Constricción Patológica/metabolismo , Constricción Patológica/patología , Angiografía Coronaria , Trombosis Coronaria/complicaciones , Trombosis Coronaria/metabolismo , Vasos Coronarios/metabolismo , Vasos Coronarios/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Placa Aterosclerótica/complicaciones , Placa Aterosclerótica/metabolismo , Plasma Rico en Plaquetas/metabolismoRESUMEN
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its resultant clinical presentation, coronavirus disease 2019 (COVID-19), is an emergent cause of mortality worldwide. Cardiac complications secondary to this infection are common; however, the underlying mechanisms of such remain unclear. A detailed cardiac evaluation of a series of individuals with COVID-19 undergoing postmortem evaluation is provided, with 4 aims: (1) describe the pathological spectrum of the myocardium; (2) compare with an alternate viral illness; (3) investigate angiotensin-converting enzyme 2 expression; and (4) provide the first description of the cardiac findings in patients with cleared infection. METHODS: Study cases were identified from institutional files and included COVID-19 (n=15: 12 active, 3 cleared), influenza A/B (n=6), and nonvirally mediated deaths (n=6). Salient information was abstracted from the medical record. Light microscopic findings were recorded. An angiotensin-converting enzyme 2 immunohistochemical H-score was compared across cases. Viral detection encompassed SARS-CoV-2 immunohistochemistry, ultrastructural examination, and droplet digital polymerase chain reaction. RESULTS: Male sex was more common in the COVID-19 group (P=0.05). Nonocclusive fibrin microthrombi (without ischemic injury) were identified in 16 cases (12 COVID-19, 2 influenza, and 2 controls) and were more common in the active COVID-19 cohort (P=0.006). Four active COVID-19 cases showed focal myocarditis, whereas 1 case of cleared COVID-19 showed extensive disease. Arteriolar angiotensin-converting enzyme 2 endothelial expression was lower in COVID-19 cases than in controls (P=0.004). Angiotensin-converting enzyme 2 myocardial expression did not differ by disease category, sex, age, or number of patient comorbidities (P=0.69, P=1.00, P=0.46, P=0.65, respectively). SARS-CoV-2 immunohistochemistry showed nonspecific staining, whereas ultrastructural examination and droplet digital polymerase chain reaction were negative for viral presence. Four patients (26.7%) with COVID-19 had underlying cardiac amyloidosis. Cases with cleared infection had variable presentations. CONCLUSIONS: This detailed histopathologic, immunohistochemical, ultrastructural, and molecular cardiac series showed no definitive evidence of direct myocardial infection. COVID-19 cases frequently have cardiac fibrin microthrombi, without universal acute ischemic injury. Moreover, myocarditis is present in 33.3% of patients with active and cleared COVID-19 but is usually limited in extent. Histological features of resolved infection are variable. Cardiac amyloidosis may be an additional risk factor for severe disease.
Asunto(s)
COVID-19 , Trombosis Coronaria , Fibrina/metabolismo , Miocardio , SARS-CoV-2/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enzima Convertidora de Angiotensina 2/biosíntesis , COVID-19/metabolismo , COVID-19/mortalidad , COVID-19/patología , Niño , Preescolar , Trombosis Coronaria/metabolismo , Trombosis Coronaria/mortalidad , Trombosis Coronaria/patología , Femenino , Regulación Enzimológica de la Expresión Génica , Humanos , Inmunohistoquímica , Lactante , Masculino , Persona de Mediana Edad , Miocardio/metabolismo , Miocardio/patologíaRESUMEN
Background The circulating level of soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) is a valuable biomarker of acute myocardial infarction (AMI). The most electronegative low-density lipoprotein, L5, signals through LOX-1 to trigger atherogenesis. We examined the characteristics of LOX-1 and the role of L5 in aspirated coronary thrombi of AMI patients. Methods and Results Intracoronary thrombi were aspirated by performing interventional thrombosuction in patients with ST-segment-elevation myocardial infarction (STEMI; n=32) or non-ST-segment-elevation myocardial infarction (n=12). LOX-1 level and the ratio of sLOX-1 to membrane-bound LOX-1 were higher in thrombi of STEMI patients than in those of non-ST-segment-elevation myocardial infarction patients. In all aspirated thrombi, LOX-1 colocalized with apoB100. When we explored the role of L5 in AMI, deconvolution microscopy showed that particles of L5 but not L1 (the least electronegative low-density lipoprotein) quickly formed aggregates prone to retention in thrombi. Treating human monocytic THP-1 cells with L5 or L1 showed that L5 induced cellular adhesion and promoted the differentiation of monocytes into macrophages in a dose-dependent manner. In a second cohort of AMI patients, the L5 percentage and plasma concentration of sLOX-1 were higher in STEMI patients (n=33) than in non-ST-segment-elevation myocardial infarction patients (n=25), and sLOX-1 level positively correlated with L5 level in AMI patients. Conclusions The level of LOX-1 and the ratio of sLOX-1 to membrane-bound LOX-1 in aspirated thrombi, as well as the circulating level of sLOX-1 were higher in STEMI patients than in non-ST-segment-elevation myocardial infarction patients. L5 may play a role in releasing a high level of sLOX-1 into the circulation of STEMI patients.
Asunto(s)
Membrana Celular/metabolismo , Trombosis Coronaria/metabolismo , Infarto del Miocardio con Elevación del ST/metabolismo , Receptores Depuradores de Clase E/metabolismo , Apolipoproteína B-100/metabolismo , Biomarcadores/metabolismo , Diferenciación Celular , Trombosis Coronaria/terapia , Femenino , Humanos , Lipoproteínas LDL/análisis , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Infarto del Miocardio con Elevación del ST/terapia , Receptores Depuradores de Clase E/sangre , Succión , Células THP-1 , Trombectomía , Regulación hacia ArribaRESUMEN
Primary percutaneous coronary intervention (PPCI) is a pivotal treatment in ST-segment elevation myocardial infarction (STEMI) patients. However, in hyperglycemic-STEMI patients, the incidence of death is still significant. Here, the involvement of sirtuin 1 (SIRT1) and miR33 on the pro-inflammatory/pro-coagulable state of the coronary thrombus was investigated. Moreover, 1-year outcomes in hyperglycemic STEMI in patients subjected to thrombus aspiration before PPCI were evaluated. Results showed that hyperglycemic thrombi displayed higher size and increased miR33, reactive oxygen species, and pro-inflammatory/pro-coagulable markers. Conversely, the hyperglycemic thrombi showed a lower endothelial SIRT1 expression. Moreover, in vitro experiments on endothelial cells showed a causal effect of SIRT1 modulation on the pro-inflammatory/pro-coagulative state via hyperglycemia-induced miR33 expression. Finally, SIRT1 expression negatively correlated with STEMI outcomes. These observations demonstrate the involvement of the miR33/SIRT1 pathway in the increased pro-inflammatory and pro-coagulable state of coronary thrombi in hyperglycemic STEMI patients.
Asunto(s)
Trombosis Coronaria/patología , Hiperglucemia/patología , MicroARNs/metabolismo , Infarto del Miocardio/patología , Sirtuina 1/metabolismo , Línea Celular , Estudios de Cohortes , Trombosis Coronaria/metabolismo , Células Endoteliales/metabolismo , Silenciador del Gen , Humanos , Hiperglucemia/metabolismo , MicroARNs/genética , Infarto del Miocardio/metabolismo , Sirtuina 1/genéticaRESUMEN
Background Cardiac magnetic resonance ( CMR) differentiates neoplasm from thrombus via contrast enhancement; positron emission tomography ( PET) assesses metabolism. The relationship between CMR contrast enhancement and metabolism on PET is unknown. Methods and Results The population included 121 cancer patients undergoing CMR and 18F-fluorodeoxyglucose (18F- FDG) - PET , including 66 with cardiac masses and cancer-matched controls. Cardiac mass etiology (neoplasm, thrombus) on CMR was defined by late gadolinium enhancement; PET was read blinded to CMR for diagnostic performance, then colocalized to measure FDG avidity. Of CMR -evidenced thrombi (all nonenhancing), none were detected by PET . For neoplasm, PET yielded reasonable sensitivity (70-83%) and specificity (75-88%). Lesions undetected by PET were more likely to be highly mobile ( P=0.001) despite similar size ( P=0.33). Among nonmobile neoplasms, PET sensitivity varied in relation to extent of CMR -evidenced avascularity; detection of diffusely enhancing or mixed lesions was higher versus predominantly avascular neoplasms (87% versus 63%). Colocalized analyses demonstrated 2- to 4-fold higher FDG uptake in neoplasm versus thrombus ( P<0.001); FDG uptake decreased stepwise when neoplasms were partitioned based on extent of avascularity on late gadolinium enhancement CMR ( P≤0.001). Among patients with neoplasm, signal-to-noise ratio on late gadolinium enhancement CMR moderately correlated with standardized uptake values on PET ( r=0.42-0.49, P<0.05). Mortality was higher among patients with CMR -evidenced neoplasm versus controls (hazard ratio: 1.99 [95% CI, 1.1-3.6]; P=0.03) despite nonsignificant differences when partitioned via FDG avidity (hazard ratio: 1.56 [95% CI, 0.85-2.74]; P=0.16). Among FDG-positive neoplasms detected concordantly with CMR , mortality risk versus cancer-matched controls was equivalently increased (hazard ratio: 2.12 [95% CI, 1.01-4.44]; P=0.047). Conclusions CMR contrast enhancement provides a criterion for neoplasm that parallels FDG -evidenced metabolic activity and stratifies prognosis. Extent of tissue avascularity on late gadolinium enhancement CMR affects cardiac mass identification by FDG - PET .
Asunto(s)
Medios de Contraste/administración & dosificación , Trombosis Coronaria/diagnóstico por imagen , Metabolismo Energético , Neoplasias Cardíacas/diagnóstico por imagen , Imagen por Resonancia Cinemagnética , Miocardio/metabolismo , Tomografía de Emisión de Positrones , Imagen de Cuerpo Entero , Adulto , Anciano , Estudios de Casos y Controles , Toma de Decisiones Clínicas , Medios de Contraste/metabolismo , Trombosis Coronaria/metabolismo , Trombosis Coronaria/mortalidad , Trombosis Coronaria/terapia , Diagnóstico Diferencial , Femenino , Fluorodesoxiglucosa F18/administración & dosificación , Fluorodesoxiglucosa F18/metabolismo , Neoplasias Cardíacas/metabolismo , Neoplasias Cardíacas/mortalidad , Neoplasias Cardíacas/terapia , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Radiofármacos/administración & dosificación , Radiofármacos/metabolismo , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: The tightly packed arrays of polyhedral erythrocytes, polyhedrocytes, formed during thrombus contraction, have been detected in some intracoronary thrombi (ICT) obtained from patients with ST-segment elevation myocardial infarction (STEMI). We sought to investigate determinants of polyhedrocyte content in ICT and its association with reperfusion in STEMI. METHODS: We assessed the composition of ICT obtained during thrombectomy within 12 h since the symptom onset in 110 STEMI patients, following 300 mg of aspirin (n = 110) and 600 mg of clopidogrel (n = 75). The predominance of fibrin, erythrocytes, polyhedrocytes or platelets was evaluated using scanning electron microscopy. RESULTS: Polyhedrocytes were found in 34 (30.9%) ICT, in which they covered 20-50% (median 38.8%) fields of view. Patients with polyhedrocytes in ICT had lower median minimal reference infarct-related artery (IRA) diameter by 20% (p < 0.0001) and area by 31% (p < 0.0001) versus those without polyhedrocytes. Time of ischemia showed association with the polyhedrocyte content (r = 0.26, p = 0.007). By multivariate analysis, minimal IRA diameter (ß = - 0.50, p < 0.0001) and ischemia time (ß = 0.20, p = 0.035) independently affected polyhedrocyte content in ICT (R2 = 0.45, p < 0.0001). Patients with ischemia time of > 3 h and polyhedrocytes present in ICT had more frequently TIMI-2/3 flow after thrombus aspiration (96% vs. 67%, p = 0.02) and final TIMI-2/3 myocardial perfusion grade (92% vs. 57%, p = 0.044) versus those without polyhedrocytes. CONCLUSIONS: Our findings indicate that the presence of polyhedrocytes in ICT, observed in one-third of STEMI patients, is associated with smaller minimal IRA diameter, prolonged ischemia and their formation in late presenters is associated with more effective thrombus aspiration and better myocardial reperfusion.
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Trombosis Coronaria/metabolismo , Eritrocitos/ultraestructura , Intervención Coronaria Percutánea/métodos , Infarto del Miocardio con Elevación del ST/diagnóstico , Trombectomía/métodos , Angiografía Coronaria , Trombosis Coronaria/complicaciones , Trombosis Coronaria/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Microscopía Electrónica de Rastreo , Persona de Mediana Edad , Estudios Retrospectivos , Infarto del Miocardio con Elevación del ST/etiología , Infarto del Miocardio con Elevación del ST/cirugíaAsunto(s)
Clopidogrel/administración & dosificación , Trombosis Coronaria/prevención & control , Intervención Coronaria Percutánea/instrumentación , Variantes Farmacogenómicas , Inhibidores de Agregación Plaquetaria/administración & dosificación , Polimorfismo de Nucleótido Simple , Stents , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Anciano , Clopidogrel/efectos adversos , Clopidogrel/farmacocinética , Trombosis Coronaria/etiología , Trombosis Coronaria/genética , Trombosis Coronaria/metabolismo , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2B6/genética , Citocromo P-450 CYP2B6/metabolismo , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Intervención Coronaria Percutánea/efectos adversos , Farmacogenética , Fenotipo , Proyectos Piloto , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/farmacocinética , Medición de Riesgo , Factores de RiesgoRESUMEN
The recognition that obstructive disease of the epicardial coronary arteries, causing ischaemic heart disease, can be treated with a percutaneous coronary intervention (PCI) has been a major discovery in cardiology in the last 40 years contributing, in particular, to the reduction of mortality associated to acute myocardial infarction (AMI). However, even in the era of drug-eluting stent (DES) implantation, a sizable proportion of patients who undergo PCI may develop late or very late post-implantation complications, that occur in the form of restenosis, neoatherosclerosis, and/or in-stent thrombosis. Such complications are clinically relevant since they can cause AMI and negatively impact on the outcome. The underlying pathophysiological mechanisms are complex but related to inhibition of neointimal proliferation by DES that, on the hand, reduces the rate of in-stent restenosis, but, on the other hand, causes dysfunctional vessel healing, persistent inflammation, platelet activation, and adverse immunological responses. Multiple approaches have been developed or are under evaluation to target DES-related complications including pharmacotherapy, procedure-related imaging methods, novel stent designs, and drug-delivery methods. The aim of this review is to provide an update on the latest preclinical, translational, and clinical pharmacotherapeutic developments in this setting that target novel cellular mechanisms and pathways that might contribute to neoatherosclerosis. Due to the importance of secondary prevention in the reduction of DES-associated complications, this review also provides a short overview of pharmacological agents that are established or currently being investigated in this regard.
Asunto(s)
Enfermedad de la Arteria Coronaria/cirugía , Reestenosis Coronaria/prevención & control , Trombosis Coronaria/prevención & control , Vasos Coronarios/cirugía , Stents Liberadores de Fármacos/efectos adversos , Intervención Coronaria Percutánea/efectos adversos , Intervención Coronaria Percutánea/instrumentación , Placa Aterosclerótica , Prevención Secundaria/métodos , Animales , Enfermedad de la Arteria Coronaria/metabolismo , Enfermedad de la Arteria Coronaria/patología , Enfermedad de la Arteria Coronaria/fisiopatología , Reestenosis Coronaria/metabolismo , Reestenosis Coronaria/patología , Reestenosis Coronaria/fisiopatología , Trombosis Coronaria/metabolismo , Trombosis Coronaria/patología , Trombosis Coronaria/fisiopatología , Vasos Coronarios/metabolismo , Vasos Coronarios/patología , Vasos Coronarios/fisiopatología , Humanos , Neointima , Diseño de Prótesis , Factores de Riesgo , Resultado del TratamientoRESUMEN
Dual antiplatelet therapy with aspirin and an adenosine diphosphate (ADP) P2Y12 receptor antagonist reduces ischemic events in patients with acute coronary syndrome. Previous evidence from our group, obtained in a preclinical model of recurrent platelet-mediated thrombosis, demonstrated that GLS-409, a diadenosine tetraphosphate derivative that inhibits both P2Y1 and P2Y12 ADP receptors, may be a novel and promising antiplatelet drug candidate. However, the salutary antiplatelet effects of GLS-409 were accompanied by a trend toward an unfavorable increase in bleeding. The goals of this study were to: 1) provide proof-of-concept that the efficacy of GLS-409 may be maintained at lower dose(s), not accompanied by an increased propensity to bleeding; and 2) establish the extent and kinetics of the reversibility of human platelet inhibition by the agent. Lower doses of GLS-409 were identified that inhibited in vivo recurrent coronary thrombosis with no increase in bleeding time. Human platelet inhibition by GLS-409 was reversible, with rapid recovery of platelet reactivity to ADP, as measured by platelet surface activated GPIIb-IIIa and platelet surface P-selectin. These data support the concept that GLS-409 warrants further, larger-scale investigation as a novel, potential therapy in acute coronary syndromes.
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Trombosis Coronaria/veterinaria , Fosfatos de Dinucleósidos/uso terapéutico , Enfermedades de los Perros/tratamiento farmacológico , Activación Plaquetaria/efectos de los fármacos , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Animales , Trombosis Coronaria/tratamiento farmacológico , Trombosis Coronaria/metabolismo , Enfermedades de los Perros/metabolismo , Perros , Femenino , Humanos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Receptores Purinérgicos P2Y1/metabolismo , Receptores Purinérgicos P2Y12/metabolismoRESUMEN
INTRODUCTION: High mobility group box 1 (HMGB1) is a member of the HMGB family that is involved in inflammatory disease-related thrombosis. We hypothesize that HMGB1 and its downstream factors are associated with thrombosis in atrial fibrillation (AF). MATERIALS AND METHODS: Our experimental materials were the left atrial appendage (LAA) tissues from patients undergoing valve replacement. The samples were divided into 3 groups: a sinus rhythm group (nâ=â15), an AF(+)thrombus(-)group (nâ=â15), and an AF(+) thrombus (+)group (nâ=â15). The expression of HMGB1, Toll-like receptor 4 (TLR4), advanced glycation end product (RAGE), myeloid differentiation factor 88 (MyD88), nuclear factor κB (NFκB), p-NFκB, and tissue factor (TF) were detected by Western blot and immunohistochemical (IHC) staining. The expressions of interleukin-1 beta, interleukin 6, and tumor necrosis factor-alpha were detected by quantitative real-time PCR. RESULTS: The Western blots revealed significantly higher expressions of HMGB1, MyD88, p-NFκB/NFκB, and TF in the AF(+)thrombus(+) group than in the other 2 groups. However, no differences in TLR4 or RAGE expression were found between the groups. IHC staining also revealed higher expressions of HMGB1 and TF in the AF(+)thrombus(+) group. The increased mRNA expressions of classic inflammatory factors (i.e., interleukin-1 beta, interleukin 6, and tumor necrosis factor-alpha) in AF(+)thrombus(+) group further validated the correlation between inflammation and thrombi in atrial fibrillation. CONCLUSIONS: HMGB1 was associated with thrombosis in patients with AF via the MyD88/NFκB pathway after adjustment for cardiac and extra cardiac inflammation variables.
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Fibrilación Atrial/metabolismo , Trombosis Coronaria/metabolismo , Proteína HMGB1/metabolismo , Adulto , Anciano , Fibrilación Atrial/complicaciones , Estudios de Casos y Controles , Trombosis Coronaria/complicaciones , Femenino , Productos Finales de Glicación Avanzada/metabolismo , Humanos , Interleucinas/metabolismo , Masculino , Persona de Mediana Edad , Factor 88 de Diferenciación Mieloide/metabolismo , FN-kappa B/metabolismo , Tromboplastina/metabolismo , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Thrombus is one of main causes of death in the world and also a vital trouble of biomaterials application in vivo. Recently, effect of fullerenol nanomaterials on anticoagulation was found in our research through extension of bleeding times in treated Sprague-Dawley rats via intravenous injection. Inhibiting of fullerenols on thrombosis was ascertained further by thromboembolism model. Effects of fullerenols on intrinsic and extrinsic pathway were distinct in prolonging activated partial thromboplastin time and prothrombin time, which supported that fullerenols induced defects in both pathways. Inhibited activities of activated coagulation factor X (FXa) and thrombin were verified by experiments in vitro and AutoDock Vina. The results suggest that fullerenols depending on small size and certainly surface property occupied the active domain of FXa and thrombin to block their activity; further, thrombosis was inhibited. This putative mechanism offers an insight into how fullerenol NPs were utilized further in biomedical applications.
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Anticoagulantes/administración & dosificación , Coagulación Sanguínea , Trombosis Coronaria/tratamiento farmacológico , Factor Xa/química , Fulerenos/administración & dosificación , Nanopartículas/administración & dosificación , Trombina/antagonistas & inhibidores , Animales , Anticoagulantes/química , Trombosis Coronaria/metabolismo , Trombosis Coronaria/patología , Fulerenos/química , Nanopartículas/química , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Manual thrombus aspiration during primary percutaneous intervention provides us with aspirated thrombus sample, that may contain material from the disrupted plaque. Immunohistopathological analysis of thrombus can yield valuable information about the clinical and cardiovascular outcomes and possible mechanisms of myocardial infarction. MATERIAL AND METHODS: We studied and analysed the immunohistopathological features of coronary thrombus aspirated from patients undergoing primary percutaneous coronary angioplasty. Immunohistological staining included markers namely CD68, SMA and CD34 for macrophages, smooth muscle actin and endothelium, respectively. Major adverse cardiac events, angiographic outcome and infarct size were also noted. RESULTS: Fifty-three patients (Mean age - 51.3±13years; males-47) who underwent primary percutaneous coronary intervention with aspiration thrombectomy were enrolled. Thrombus was successfully aspirated in 40 of 53 patients (75.4%). Patients with successful thrombus aspiration had higher ST-segment resolution (≥50%) as compared to patients with failed thrombus aspiration. Presence of RBC-rich thrombus on microscopy was more commonly associated with post-procedure TIMI flow of <2 as compared to patients with fibrin-rich thrombus and a trend towards lower myocardial blush grade<2 (P=0.10), and a significantly higher final infarct size (37.5±5% vs 25±15%; P=0.04 of myocardium) on nuclear scan. Immunohistology revealed presence of plaque material in 72% (26/36) of the samples. CONCLUSIONS: Immunohistopathological evaluation of intracoronary thrombus may be of prognostic importance. High prevalence of plaque material in the aspirated intracoronary thrombus suggests plaque rupture as a possible etiology for vessel occlusion in these patients. SHORT SUMMARY: Immunohistopathological evaluation of intracoronary thrombus reveals high prevalence of plaque material in the aspirated intracoronary thrombus suggesting plaque rupture as a possible etiology for vessel occlusion in Indian STEMI patients.
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Enfermedad de la Arteria Coronaria/terapia , Trombosis Coronaria/terapia , Inmunohistoquímica , Intervención Coronaria Percutánea , Placa Aterosclerótica , Infarto del Miocardio con Elevación del ST/terapia , Trombectomía/métodos , Actinas/análisis , Adulto , Antígenos CD/análisis , Antígenos CD34/análisis , Antígenos de Diferenciación Mielomonocítica/análisis , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/metabolismo , Enfermedad de la Arteria Coronaria/patología , Trombosis Coronaria/metabolismo , Trombosis Coronaria/patología , Femenino , Humanos , India , Masculino , Persona de Mediana Edad , Intervención Coronaria Percutánea/efectos adversos , Valor Predictivo de las Pruebas , Estudios Prospectivos , Factores de Riesgo , Rotura Espontánea , Infarto del Miocardio con Elevación del ST/metabolismo , Infarto del Miocardio con Elevación del ST/patología , Succión , Trombectomía/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Although drug-eluting stents have dramatically reduced the rates of restenosis and target lesion revascularization, they are associated with stent thrombosis (ST), a catastrophic event likely due to delayed endothelialization and chronic inflammation caused by the polymer and the metal scaffolds. To increase the safety and efficacy of stents, polymer-free dual drug-eluting stents (DDES) have been developed. METHODS: A total 160 stents (Bare-metal stents (BMS), polymer-free probucol stents (PrES), sirolimus-eluting stents (SES) and DDES) were randomly implanted in the coronary arteries of 80 pigs. 14, 28, 90 and 191 days after implantation, QCA and OCT evaluations were performed in 20 pigs respectively, and the arteries were harvested for scanning electron microscope (SEM), histomorphology, histopathology analyses and for the relative expression of CD31, CD34 and CD133 on mRNA and protein levels. RESULTS: At the 14-day time point, there were significant differences in the strut rate coverage (p = 0.011), with greater coverage in the PrES than in the SES group (53.2%vs. 20.3%, p = 0.002). As well, there were no significant differences in the expression of CD31, CD34 and CD133 between groups in mRNA and protein level. CONCLUSIONS: DDES were as safe as BMS and SES, but they did not further improve the endothelialization of the stented coronary arteries in the porcine model.
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Fármacos Cardiovasculares/administración & dosificación , Vasos Coronarios , Stents Liberadores de Fármacos , Metales , Intervención Coronaria Percutánea/instrumentación , Probucol/administración & dosificación , Sirolimus/administración & dosificación , Stents , Antígeno AC133/genética , Antígeno AC133/metabolismo , Animales , Antígenos CD34/genética , Antígenos CD34/metabolismo , Angiografía Coronaria , Trombosis Coronaria/diagnóstico por imagen , Trombosis Coronaria/etiología , Trombosis Coronaria/metabolismo , Trombosis Coronaria/patología , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/metabolismo , Vasos Coronarios/ultraestructura , Femenino , Masculino , Microscopía Electrónica de Rastreo , Modelos Animales , Intervención Coronaria Percutánea/efectos adversos , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/genética , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Diseño de Prótesis , ARN Mensajero/genética , ARN Mensajero/metabolismo , Porcinos , Porcinos Enanos , Factores de Tiempo , Tomografía de Coherencia ÓpticaRESUMEN
SIGNIFICANCE: The incidence of cardiovascular events (CVEs) increases with age, representing the main cause of death in an elderly population. Aging is associated with overproduction of reactive oxygen species (ROS), which may affect clotting and platelet activation, and impair endothelial function, thus predisposing elderly patients to thrombotic complications. Recent Advances: There is increasing evidence to suggest that aging is associated with an imbalance between oxidative stress and antioxidant status. Thus, upregulation of ROS-producing enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and myeloperoxidase, along with downregulation of antioxidant enzymes, such as superoxide dismutase and glutathione peroxidase, occurs during aging. This imbalance may predispose to thrombosis by enhancing platelet and clotting activation and eliciting endothelial dysfunction. Recently, gut-derived products, such as trimethylamine N-oxide (TMAO) and lipopolysaccharide, are emerging as novel atherosclerotic risk factors, and gut microbiota composition has been shown to change by aging, and may concur with the increased cardiovascular risk in the elderly. CRITICAL ISSUES: Antioxidant treatment is ineffective in patients at risk or with cardiovascular disease. Further, anti-thrombotic treatment seems to work less in the elderly population. FUTURE DIRECTIONS: Interventional trials with antioxidants targeting enzymes implicated in aging-related atherothrombosis are warranted to explore whether modulation of redox status is effective in lowering CVEs in the elderly. Antioxid. Redox Signal. 27, 1083-1124.
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Envejecimiento/metabolismo , Antioxidantes/metabolismo , Trombosis Coronaria/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Anciano , Anciano de 80 o más Años , Animales , Ensayos Clínicos como Asunto , Trombosis Coronaria/tratamiento farmacológico , Microbioma Gastrointestinal , Regulación Enzimológica de la Expresión Génica , Humanos , Estrés Oxidativo , Factores de RiesgoRESUMEN
The clinical impact of in-stent thrombosis is high because it is associated with high mortality and 20 % of the patients suffer a recurrent event within the two following years. The aim of this study was to characterise the morphologic and proteomic profile of in-stent thrombi (IST) in comparison to thrombi developed on native coronary arteries (CT) to identify a differential molecular signature. The study included 45 patients with ST-elevation-myocardial-infarction (STEMI) treated by primary-percutaneous-intervention and thrombus aspiration: 21 had IST and 24 had CT. Thrombi were characterised by morphologic immunohistochemical analysis and differential proteomic profiling (2-DE+MALDI-TOF/TOF). Bioinformatic analysis revealed differences in proteins related to oxidative-stress and cell death/survival. IST showed a higher content of structural proteins (gelsolin, actin-cytoplasmic-1, tropomyosin, and myosin) together with an imbalance in redox-homeostasis related proteins (increased superoxide-dismutase and decreased peroxiredoxin-2 thrombus content), and a coordinated increase of chaperones (HSP60 and HSC70) and cellular quality control-related proteins (26S-protease-regulatory-subunit-7). These changes were reflected into a significant decrease in HSC70 systemic levels and a significant increase in advanced-oxidation-protein-products (AOPP) indicative of increased oxidative stress-mediated protein damage in IST. Our results reveal an imbalance in redox-related proteins indicative of an exacerbated oxidative-stress that leads to an accumulation of AOPP serum levels in IST. Moreover, the coordinated increase in chaperones and regulatory proteins reflects the activation of intracellular protection mechanisms to maintain protein integrity in IST. The failure to counterbalance the stress situation could trigger cellular apoptosis leading to the destabilization of the thrombus and to a worse prognosis of IST-STEMI-patients.
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Trombosis Coronaria/metabolismo , Inmunidad Innata , Estrés Oxidativo , Intervención Coronaria Percutánea/instrumentación , Infarto del Miocardio con Elevación del ST/terapia , Stents , Biomarcadores/metabolismo , Biología Computacional , Trombosis Coronaria/diagnóstico por imagen , Trombosis Coronaria/etiología , Trombosis Coronaria/terapia , Femenino , Fibrinógeno/metabolismo , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Chaperonas Moleculares/metabolismo , Intervención Coronaria Percutánea/efectos adversos , Proteómica/métodos , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Trombectomía , Resultado del TratamientoRESUMEN
AIMS: Hyperlipidaemia enhances susceptibility to thrombosis, while platelet oxidixed LDL (oxLDL) binding in acute coronary syndrome (ACS) correlates with activation status. This study explores the platelet lipidome in symptomatic coronary artery disease (CAD) patients and the functional consequences of the chemokine CXCL12 and its receptors CXCR-4/-7 on lipid uptake in platelets. METHODS AND RESULTS: Platelet-oxLDL detected by flow cytometry was enhanced (P = 0.04) in CAD patients, moderately correlated with platelet CXCR7 surface expression (ρ = 0.39; P < 0.001), while inversely with CXCR4 (ρ = 0.35; P < 0.001). Platelet-oxLDL was elevated (P = 0.01) in ACS patients with angiographic evidence of intracoronary thrombi. Ex vivo analysis of intracoronary thrombi sections revealed oxLDL deposition in platelet-enriched areas verified by immunofluorescence confocal microscopy. LDL-oxLDL uptake enhanced reactive oxygen species, mitochondrial superoxide generation, intraplatelet LDL to oxLDL conversion, and lipid peroxidation, counteracted by SOD2-mimetic MnTMPyP. Lipidomic analysis revealed enhanced intraplatelet-oxidized phospholipids, cholesteryl esters, sphingomyelin, ceramides, di- and triacylglycerols, acylcarnitines in CAD patients compared with age-matched controls as ascertained by liquid chromatography hyphenated to high-resolution mass spectrometry. LDL-oxLDL induced degranulation, αIIbß3-integrin activation, apoptosis, thrombin generation estimated by calibrated automated thrombinoscopy, and shape change verified by live imaging using scanning ion conductance microscopy. Further, LDL-oxLDL enhanced thrombus formation ex vivo and in vivo in mice (ferric chloride-induced carotid artery injury). LDL-oxLDL enhanced platelet CXCL12 release, differentially regulated CXCR4-CXCR7 surface exposure, while CXCL12 prompted LDL-oxLDL uptake and synergistically augmented the LDL-oxLDL-induced pro-oxidative, thrombogenic impact on platelet function. CONCLUSION: An altered platelet lipidome might be associated with thrombotic disposition in CAD, a mechanism potentially regulated by CXCL12-CXCR4-CXCR7 axis.
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Plaquetas/metabolismo , Enfermedad de la Arteria Coronaria/etiología , Lipoproteínas LDL/metabolismo , Síndrome Coronario Agudo/etiología , Síndrome Coronario Agudo/metabolismo , Anciano , Estudios de Casos y Controles , Quimiocina CXCL12/metabolismo , Quimiocina CXCL12/fisiología , Enfermedad de la Arteria Coronaria/metabolismo , Trombosis Coronaria/etiología , Trombosis Coronaria/metabolismo , Femenino , Humanos , Metabolismo de los Lípidos/fisiología , Peroxidación de Lípido/fisiología , Masculino , Persona de Mediana Edad , Especies Reactivas de Oxígeno/metabolismo , Receptores CXCR/metabolismo , Receptores CXCR/fisiología , Receptores CXCR4/metabolismo , Receptores CXCR4/fisiologíaRESUMEN
Recent studies have demonstrated that inflammatory cells are a component that plays a role in thrombus formation in ST-elevation myocardial infarction (STEMI). 3-nitrotyrosine (3-NO2-Tyr), a specific marker for protein modification by nitric oxide-derived oxidants, is increased in human atherosclerotic lesions. The purpose of this study was to determine the possible association of inflammatory markers of coronary thrombi with nitroxidative stress. Intracoronary thrombus (n=51) and blood from the systemic circulation were obtained by thromboaspiration in 138 consecutive STEMI patients presenting for primary percutaneous coronary intervention (PCI). Each blood and intracoronary thrombus were measured simultaneously the following biomarkers: C-reactive protein (CRP), 3-NO2-Tyr, soluble CD 40 ligand (sCD40L), vascular cellular adhesion molecule-1 (VCAM-1) and haemoglobin content (only in coronary thrombus). Time delay in minutes from symptom onset to PCI was 244 ± 324. Serum CRP was positively correlated to CRP content in the thrombus (r= 0.395; p = 0.02) and serum sCD40L was negatively correlated to sCD40L in the thrombus (r= -0.394; p = 0.02). Patients were divided into tertiles according to thrombi 3-NO2-Tyr concentration: 1(st)tertile (<0.146ng/mg), 2(nd)tertile (0.146-0.485ng/mg) and 3(rd)tertile (>0.485ng/mg). Thus, thrombus in the highest tertile had significantly higher levels of CRP (p=0.002), VCAM-1 (p=0.003) and haemoglobin (p=0.002). In conclusion, the present study demonstrated that coronary thrombi with higher levels of 3-NO2-Tyr content often contain more inflammatory markers which could have a direct impact on the efficacy of drugs or devices used for coronary reperfusion.