RESUMEN
BACKGROUND: MicroRNA are noncoding RNA that have a significant role in both inflammatory and cardiovascular diseases. AIMS: We aimed to assess whether the inflammation-related microRNA-155 is associated with the development of adverse left ventricular (LV) remodeling following ST elevation myocardial infarction (STEMI). METHODS: Peripheral blood samples were collected in the inflammatory (day 2), proliferative (day 5), and maturation phases (6 months) after STEMI (n = 20). Granulocytes, monocytes, and lymphocytes were enumerated with flow cytometry. The changes in LV volumes were assessed with 3-D echocardiography on day 1 and after 6 months. Adverse remodeling was defined as a >20% increase in end-diastolic volume. Healthy subjects were recruited as controls. RESULTS: MicroRNA-155 measured on day 5 correlated positively with the relative change in end-diastolic volume (ρ = 0.490, p = 0.028). MicroRNA-155 (day 5) was significantly higher in patients with compared to patients without adverse LV remodeling. The expression level was similar in healthy subjects (n = 8) and in patients with LV remodeling. There was a positive correlation between microRNA-155 and the amount of monocytes (day 5, ρ = 0.463, p = 0.046). CONCLUSION: Impaired downregulation of microRNA-155 during the second phase of the post- STEMI inflammatory response is a determinant of the development of adverse LV remodeling.
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MicroARNs/sangre , Infarto del Miocardio con Elevación del ST/sangre , Infarto del Miocardio con Elevación del ST/fisiopatología , Remodelación Ventricular , Anciano , Estudios de Casos y Controles , Ecocardiografía Tridimensional , Femenino , Regulación de la Expresión Génica , Humanos , Modelos Logísticos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST/cirugía , Resultado del Tratamiento , Función Ventricular IzquierdaRESUMEN
Skeletal muscle metabolic changes are common in patients with chronic heart failure (HF). Previously, we demonstrated a functional skeletal muscle adiponectin resistance in HF patients with reduced left ventricular ejection fraction (HFrEF). We aimed to examine the impact of adiponectin receptor 1 (AdipoR1) deficiency and TNF-α treatment on adiponectin signaling, proliferative capacity, myogenic differentiation, and mitochondrial biogenesis in primary human skeletal muscle cells. Primary cultures of myoblasts and myotubes were initiated from the musculus vastus lateralis of 10 HFrEF patients (left ventricular ejection fraction; 31.30 ± 2.89%) and 10 age- and gender-matched healthy controls. Healthy control cultures were transfected with siAdipoR1 and/or exposed to TNF-α (10 ng/ml; 72 h). Primary cultures from HFrEF patients preserved the features of adiponectin resistance in vivo. AdipoR1 mRNA was negatively correlated with time to reach maximal cell index (r = -0.7319, P = 0.003). SiRNA-mediated AdipoR1 silencing reduced pAMPK (P < 0.01), AMPK activation (P = 0.046), and myoblast proliferation rate (xCELLigence Real-Time Cellular Analysis; P < 0.0001). Moreover, TNF-α decreased the mRNA expression of genes involved in glucose (APPL1, P = 0.0002; AMPK, P = 0.021), lipid (PPARα, P = 0.025; ACADM, P = 0.003), and mitochondrial (FOXO3, P = 0.018) metabolism, impaired myogenesis (MyoD1, P = 0.053; myogenin, P = 0.048) and polarized cytokine secretion toward a growth-promoting phenotype (IL-10, IL-1ß, IFN-γ, P < 0.05 for all; Meso Scale Discovery Technology). Major features of adiponectin resistance are retained in primary cultures from the skeletal muscle of HFrEF patients. In addition, our results suggest that an increased inflammatory constitution contributes to adiponectin resistance and confers alterations in skeletal muscle differentiation, growth, and function.
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Adiponectina/metabolismo , Insuficiencia Cardíaca/metabolismo , Mitocondrias Musculares/efectos de los fármacos , Desarrollo de Músculos/efectos de los fármacos , Fibras Musculares Esqueléticas/efectos de los fármacos , Biogénesis de Organelos , Músculo Cuádriceps/efectos de los fármacos , Receptores de Adiponectina/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/farmacología , Estudios de Casos y Controles , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Femenino , Regulación de la Expresión Génica , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/patología , Humanos , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Masculino , Persona de Mediana Edad , Mitocondrias Musculares/metabolismo , Mitocondrias Musculares/patología , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Fenotipo , Cultivo Primario de Células , Músculo Cuádriceps/metabolismo , Músculo Cuádriceps/patología , Interferencia de ARN , Receptores de Adiponectina/deficiencia , Receptores de Adiponectina/genética , Factores de Tiempo , TransfecciónRESUMEN
The initial promising prospect of autologous bone marrow-derived stem cell therapy in the setting of cardiovascular diseases has been overshadowed by functional shortcomings of the stem cell product. As powerful epigenetic regulators of (stem) cell function, microRNAs are valuable targets for novel therapeutic strategies. Indeed, modulation of specific miRNA expression could contribute to improved therapeutic efficacy of stem cell therapy. First, this review elaborates on the functional relevance of miRNA dysregulation in bone marrow-derived progenitor cells in different cardiovascular diseases. Next, we provide a comprehensive overview of the current evidence on the effect of specific miRNA modulation in several types of progenitor cells on cardiac and/or vascular regeneration. By elaborating on the cardioprotective regulation of progenitor cells on cardiac miRNAs, more insight in the underlying mechanisms of stem cell therapy is provided. Finally, some considerations are made regarding the potential of circulating miRNAs as regulators of the miRNA signature of progenitor cells in cardiovascular diseases.
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Enfermedades Cardiovasculares/cirugía , Terapia Genética/métodos , MicroARNs/genética , Miocardio , Miocitos Cardíacos/trasplante , Regeneración , Trasplante de Células Madre/métodos , Animales , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/patología , Enfermedades Cardiovasculares/fisiopatología , Epigénesis Genética , Regulación de la Expresión Génica , Humanos , MicroARNs/metabolismo , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patologíaRESUMEN
Heart failure (HF) is a growing health problem. Despite improved management and outcome, the number of patients with HF is expected to keep rising in the following years. In recent research, adiponectin was shown to exert beneficial effects in the cardiovascular system, but the protein was also implicated in the development and progression of HF. The objective of this review is to provide an overview of current knowledge on the role of adiponectin in HF with reduced ejection fraction. We discuss the cardioprotective and (anti-) inflammatory actions of adiponectin and its potential use in clinical diagnosis and prognosis.
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Adiponectina/sangre , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/fisiopatología , Volumen Sistólico , Adiponectina/fisiología , Biomarcadores/sangre , Enfermedad Crónica , Progresión de la Enfermedad , Humanos , Pronóstico , Factores de RiesgoRESUMEN
Childhood obesity jeopardizes a healthy future for our society's children as it is associated with increased cardiovascular morbidity and mortality later on in life. Endothelial dysfunction, the first step in the development of atherosclerosis, is already present in obese children and may well represent a targetable risk factor. Technological advancements in recent years have facilitated noninvasive measurements of endothelial homeostasis in children. Thereby this topic ultimately starts to get the attention it deserves. In this paper, we aim to summarize the latest insights on endothelial dysfunction in childhood obesity. We discuss methodological advancements in peripheral endothelial function measurement and newly identified diagnostic markers of vascular homeostasis. Finally, future challenges and perspectives are set forth on how to efficiently tackle the catastrophic rise in cardiovascular morbidity and mortality that will be inflicted on obese children if they are not treated optimally.
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Endotelio Vascular/fisiopatología , Obesidad Infantil/fisiopatología , Adolescente , Aterosclerosis/fisiopatología , Índice de Masa Corporal , Enfermedades Cardiovasculares/fisiopatología , Niño , Ejercicio Físico , Homeostasis , Humanos , Guías de Práctica Clínica como Asunto , Factores de Riesgo , Factores de TiempoRESUMEN
BACKGROUND: Exercise intolerance is an important feature in patients with chronic kidney disease (CKD) and is prognostic for both increased morbidity and mortality. Little is known about the underlying mechanisms in predialysis CKD. This study aimed to gain more insight into the role of vascular dysfunction in the exercise intolerance of predialysis CKD. In addition, vascular-related microRNAs (miRNAs)-as epigenetic regulators of exercise capacity-were analysed. METHODS: Sixty-three patients with CKD stages 1-5 and 18 healthy controls were included. Peak oxygen consumption (VO2peak) was determined by cardiopulmonary exercise testing, endothelial function by flow-mediated dilation (FMD) and arterial stiffness by carotid-femoral pulse wave velocity (PWV). Plasma miRNA levels (miR-21, miR-126, miR-146a, miR-150 and miR-210) were quantified by quantitative RT-PCR. RESULTS: VO2peak was already impaired in mild CKD (stages 1-3A) and significantly correlated with estimated glomerular filtration rate (eGFR; r = 0.525, P < 0.001). Likewise, both FMD and PWV were significantly correlated with eGFR (r = 0.319, P = 0.007 and r = -0.365, P = 0.001, respectively). In multiple regression analysis, PWV remained one of the strongest independent determinants of VO2peak (ß = -0.301, P = 0.01). Of the studied miRNA, circulating levels of miR-146a and miR-150 correlated with eGFR, PWV and VO2peak, but the association with the latter was lost when correcting for PWV. CONCLUSIONS: Arterial stiffness contributes to the observed reduced aerobic capacity in predialysis CKD, independent of age, haemoglobin levels and endothelial function and represents a promising therapeutic target for improving exercise capacity in this population. Future work is required to elucidate why higher circulating levels of miR-146a and miR-150 are associated with impaired renal function and increased arterial stiffness.
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Enfermedades Vasculares Periféricas/fisiopatología , Insuficiencia Renal Crónica/fisiopatología , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , MicroARNs/sangre , Persona de Mediana Edad , Consumo de Oxígeno , Enfermedades Vasculares Periféricas/sangre , Enfermedades Vasculares Periféricas/etiología , Resistencia Física , Esfuerzo Físico , Análisis de la Onda del Pulso , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/complicaciones , Rigidez Vascular , VasodilataciónRESUMEN
BACKGROUND: Peripheral skeletal muscle wasting is a common finding with adverse effects in chronic heart failure (HF). Whereas its clinical relevance is beyond doubt, the underlying pathophysiological mechanisms are not yet fully elucidated. We aimed to introduce and characterize the primary culture of skeletal muscle cells from individual HF patients as a supportive model to study this muscle loss. METHODS AND RESULTS: Primary myoblast and myotubes cultures were successfully propagated from the m. vastus lateralis of 6 HF patients with reduced ejection fraction (HFrEF; LVEF <45 %) and 6 age and gender-matched healthy donors. HFrEF cultures were not different from healthy donors in terms of morphology, such as myoblast size, shape and actin microfilament. Differentiation and fusion indexes were identical between groups. Myoblast proliferation in logarithmic growth phase, however, was attenuated in the HFrEF group (p = 0.032). In addition, HFrEF myoblasts are characterized by a reduced TNFR2 expression and IL-6 secretion (p = 0.017 and p = 0.016; respectively). CONCLUSION: Biopsy derived primary skeletal muscle myoblasts of HFrEF patients produce similar morphological and myogenic differentiation responses as myoblasts of healthy donors, though demonstrate loss of anti-inflammatory and proliferative activity.
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Proliferación Celular , Senescencia Celular , Insuficiencia Cardíaca/patología , Inflamación/patología , Atrofia Muscular/patología , Mioblastos Esqueléticos/patología , Músculo Cuádriceps/patología , Estudios de Casos y Controles , Células Cultivadas , Enfermedad Crónica , Femenino , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Humanos , Inflamación/metabolismo , Inflamación/fisiopatología , Interleucina-6/metabolismo , Masculino , Persona de Mediana Edad , Atrofia Muscular/metabolismo , Atrofia Muscular/fisiopatología , Mioblastos Esqueléticos/metabolismo , Factores Reguladores Miogénicos/metabolismo , Factor de Transcripción PAX3/metabolismo , Factor de Transcripción PAX7/metabolismo , Fenotipo , Cultivo Primario de Células , Músculo Cuádriceps/metabolismo , Músculo Cuádriceps/fisiopatología , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Transducción de Señal , Volumen Sistólico , Factores de Tiempo , Función Ventricular IzquierdaRESUMEN
Exercise training is an effective way to improve exercise capacity in chronic kidney disease (CKD), but the underlying mechanisms are only partly understood. In healthy subjects (HS), microRNA (miRNA or miR) are dynamically regulated following exercise and have, therefore, been suggested as regulators of cardiovascular adaptation to exercise. However, these effects were not studied in CKD before. The effect of acute exercise (i.e., an acute exercise bout) was assessed in 32 patients with CKD and 12 age- and sex-matched HS (study 1). miRNA expression in response to chronic exercise (i.e., a 3-mo exercise training program) was evaluated in 40 CKD patients (study 2). In a subgroup of study 2, the acute-exercise induced effect was evaluated at baseline and at follow-up. Plasma levels of a preselected panel miRNA, involved in exercise adaptation processes such as angiogenesis (miR-126, miR-210), inflammation (miR-21, miR-146a), hypoxia/ischemia (miR-21, miR-210), and progenitor cells (miR-150), were quantified by RT-PCR. Additionally, seven miRNA involved in similar biological processes were quantified in the subgroup of study 2. Baseline, studied miRNA were comparable in CKD and HS. Following acute exercise, miR-150 levels increased in both CKD (fold change 2.12 ± 0.39, P = 0.002; and HS: fold change 2.41 ± 0.48 P = 0.018, P for interaction > 0.05). miR-146a acutely decreased in CKD (fold change 0.92 ± 0.13, P = 0.024), whereas it remained unchanged in HS. Levels of miR-21, miR-126, and miR-210 remained unaltered. Chronic exercise did not elicit a significant change in the studied miRNA levels. However, an acute exercise-induced decrease in miR-210 was observed in CKD patients, only after training (fold change 0.76 ± 0.15). The differential expression in circulating miRNA in response to acute and chronic exercise may point toward a physiological role in cardiovascular adaptation to exercise, also in CKD.
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Terapia por Ejercicio/métodos , MicroARNs/sangre , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/terapia , Adulto , Anciano , Umbral Anaerobio , Proliferación Celular , Progresión de la Enfermedad , Prueba de Esfuerzo , Femenino , Tasa de Filtración Glomerular , Humanos , Hipoxia/genética , Hipoxia/patología , Inflamación/genética , Inflamación/patología , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Neovascularización Fisiológica/genética , Células Madre/metabolismoRESUMEN
In this large multicenter trial, we aimed to assess the effect of aerobic exercise training in stable coronary artery disease (CAD) patients on cellular markers of endothelial integrity and to examine their relation with improvement of endothelial function. Two-hundred CAD patients (left ventricular ejection fraction > 40%, 90% male, mean age 58.4 ± 9.1 yr) were randomized on a 1:1 base to a supervised 12-wk rehabilitation program of either aerobic interval training or aerobic continuous training on a bicycle. At baseline and after 12 wk, numbers of circulating CD34(+)/KDR(+)/CD45dim endothelial progenitor cells (EPCs), CD31(+)/CD3(+)/CXCR4(+) angiogenic T cells, and CD31(+)/CD42b(-) endothelial microparticles (EMPs) were analyzed by flow cytometry. Endothelial function was assessed by flow-mediated dilation (FMD) of the brachial artery. After 12 wk of aerobic interval training or aerobic continuous training, numbers of circulating EPCs, angiogenic T cells, and EMPs were comparable with baseline levels. Whereas improvement in peak oxygen consumption was correlated to improvement in FMD (Pearson r = 0.17, P = 0.035), a direct correlation of baseline or posttraining EPCs, angiogenic T cells, and EMP levels with FMD was absent. Baseline EMPs related inversely to the magnitude of the increases in peak oxygen consumption (Spearman rho = -0.245, P = 0.027) and FMD (Spearman rho = -0.374, P = 0.001) following exercise training. In conclusion, endothelial function improvement in response to exercise training in patients with CAD did not relate to altered levels of EPCs and angiogenic T cells and/or a diminished shedding of EMPs into the circulation. EMP flow cytometry may be predictive of the increase in aerobic capacity and endothelial function.
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Micropartículas Derivadas de Células/metabolismo , Enfermedad de la Arteria Coronaria/terapia , Células Progenitoras Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Terapia por Ejercicio/métodos , Anciano , Bélgica , Ciclismo , Biomarcadores/sangre , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/fisiopatología , Endotelio Vascular/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recuperación de la Función , Volumen Sistólico , Linfocitos T/metabolismo , Factores de Tiempo , Resultado del Tratamiento , Vasodilatación , Función Ventricular IzquierdaRESUMEN
Cerebral ischemia (CeI) is a major complicating event after acute brain injury (ABI) in which endothelial dysfunction is a key player. This study evaluates cellular markers of endothelial function and in vivo reactive hyperemia in patients with ABI and their relationship to the development of cerebral ischemia. We studied cellular markers of endothelial dysfunction and the peripheral reactive hyperemia index (RHI) in 26 patients with ABI at admission and after 6 and 12 days, and compared these with those of healthy volunteers (n = 15). CeI was determined clinically or by computer tomography. In patients with ABI, RHI at admission was significantly reduced compared with healthy subjects (P = 0.003), coinciding with a decrease in circulating endothelial progenitor cells (EPC; P = 0.002). The RHI recovered in eight patients without development of CeI, but failed to fully recover by day 12 in three of four patients who developed CeI. Despite recovery of the RHI within 12 days in these patients (P = 0.003), EPC count remained significantly lower after 12 days in patients with ABI (P = 0.022). CD31(+) T cells and endothelial microparticles were not different between controls and patients. No differences were noted in cellular markers of endothelial dysfunction in patients developing CeI and those not. In conclusion, patients with ABI exhibit impaired microvascular endothelial function measured as RHI and a decreased circulating level of EPC.
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Lesiones Encefálicas/complicaciones , Lesiones Encefálicas/patología , Isquemia Encefálica/etiología , Endotelio/patología , Adulto , Antígenos CD/metabolismo , Células Progenitoras Endoteliales/patología , Humanos , Persona de Mediana Edad , Índice de Severidad de la EnfermedadRESUMEN
INTRODUCTION: Coronary angiography is able to induce a systemic inflammatory response. We hypothesised that this procedure may affect monocyte and dendritic cell count and membrane-associated antigen expression. METHODS: Blood samples were obtained before and immediately after coronary angiography in twenty patients with stable angina pectoris. Cell enumeration and antigen expression levels were evaluated by flow cytometry. Plasma levels of soluble CD14 and interleukin-6 were quantified by ELISA. RESULTS: The absolute and relative numbers of circulating monocytes (Mon1, Mon2 and Mon3 subsets) and dendritic cells (myeloid and plasmacytoid subsets) were not significantly different pre-versus post-angiography. Expression of CD14 on Mon1 and Mon2 decreased significantly by 12.01% (P = 0.002) and 13.01% (P=0.012), respectively. CD16 expression on Mon2 (+10.53%; P=0.017) and Mon3 (+12.58%; P<0.001) increased. CD45 expressed by monocytic and dendritic cells was lowered (-5.80% and P = 0.001, -11.49% and P < 0.001, respectively). The level of plasma IL-6 decreased significantly (P = 0.002). The reduction in sCD14 was not significant (P = 0.054). CONCLUSION: Coronary angiography leads to changes in surface expression of CD14, CD16 and CD45. These findings underline the importance of blood collection prior to the angiographic procedure when aiming to study the functional analysis of monocyte and dendritic cell numbers by flow cytometry.
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Angiografía Coronaria , Células Dendríticas/química , Antígenos Comunes de Leucocito/sangre , Receptores de Lipopolisacáridos/sangre , Monocitos/química , Receptores de IgG/sangre , Anciano , Recuento de Células , Membrana Celular/química , Femenino , Citometría de Flujo , Humanos , MasculinoRESUMEN
OBJECTIVE: To examine the degree of microvascular endothelial dysfunction in relation to classical cardiovascular risk factors, arterial stiffness, and numbers of circulating endothelial progenitor cells (EPCs) and endothelial microparticles (EMPs), in obese and normal-weight children. STUDY DESIGN: Cross-sectional study with 57 obese (15.2±1.4 years) and 30 normal-weight children (15.4±1.5 years). The principal outcome was microvascular endothelial function measured with peripheral arterial tonometry. Fasting blood samples were taken for biochemical analysis and EMPs (CD31+/CD42b- particles) and EPCs (CD34+/KDR+/CD45dim/- cells) flow cytometry. Characteristics between groups were compared by use of the appropriate independent samples test; a stepwise multiple regression analysis was used to determine independent predictors of microvascular endothelial function. RESULTS: Microvascular endothelial function was significantly impaired in obese children and inversely correlated with body mass index Z scores (r=-0.249; P=.021) and systolic blood pressure (r=-0.307; P=.004). The number of EPCs was significantly lower in obese children and correlated with endothelial function (r=0.250; P=.022), and the number of EMPs was significantly greater in obese children and correlated inversely with endothelial function (r=-0.255; P=.021). Multivariate analysis revealed that systolic blood pressure and numbers of circulating EPCs and EMPs are important determinants of endothelial function. CONCLUSION: Obese children demonstrate impaired endothelial microvascular function, increased arterial stiffness, fewer EPCs, and more EMPs. Besides systolic blood pressure, EPC and EMP counts independently predict the presence of microvascular endothelial dysfunction.
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Micropartículas Derivadas de Células/fisiología , Células Endoteliales/fisiología , Endotelio Vascular/fisiopatología , Obesidad Infantil/fisiopatología , Células Madre/fisiología , Rigidez Vascular/fisiología , Adolescente , Presión Sanguínea , Niño , Estudios Transversales , Femenino , Citometría de Flujo , Humanos , Masculino , Manometría , Análisis de RegresiónRESUMEN
OBJECTIVES: To assess the late postinterventional response to iliac stenting in atheromatous rabbits using the Xience V everolimus-eluting stent (Xience V EES; Abbott Vascular) and the Resolute zotarolimus-eluting stent (Resolute ZES; Medtronic Vascular) with the MultiLink Vision bare metal stent (BMS; Abbott Vascular) as a reference. BACKGROUND: Xience V EES and Resolute ZES were developed to overcome shortcomings of first-generation DES. METHODS: Functional and microscopic changes were assessed by organ bath experiments and histopathologic examination. Gene expression was investigated using RT-PCR. RESULTS: After 91 days, re-endothelialization was nearly complete (BMS: 93 ± 3%; Resolute ZES: 92 ± 2%; Xience V EES: 94 ± 3%; P = 0.10). Neointima thickness was similar in Resolute ZES (0.17 ± 0.08 mm) and BMS (0.17 ± 0.09 mm), and reduced in Xience V EES (0.03 ± 0.01 mm; P < 0.0001). Xience V EES had less peri-strut inflammation compared with BMS (P = 0.001) and Resolute ZES (P = 0.0001), while arterial segments distal to Xience V EES were more sensitive to acetylcholine than those distal to BMS and Resolute ZES (P = 0.02). Lectin-like oxidized receptor-1 was overexpressed in stented arteries (P < 0.001), whereas thrombomodulin was downregulated in Resolute ZES (P = 0.01) and BMS (P = 0.02) compared to unstented arteries of rabbits on regular chow. No significant changes were seen for vascular cell adhesion molecule-1, nitric oxide synthase 3, or endothelin-1. CONCLUSIONS: At 3-month follow-up, nearly complete re-endothelialization was achieved for all stent groups. Xience V EES induced greater suppression of neointimal growth and peri-strut inflammation, higher vasorelaxation to acetylcholine, and expression of thrombomodulin at the level of unstented controls.
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Aterosclerosis/terapia , Stents Liberadores de Fármacos , Everolimus/administración & dosificación , Arteria Ilíaca/patología , Sirolimus/análogos & derivados , Acetilcolina/farmacología , Angioplastia de Balón , Animales , Aterosclerosis/patología , Modelos Animales de Enfermedad , Regulación hacia Abajo , Endotelio Vascular/patología , Inflamación/patología , Neointima/patología , Conejos , Receptores Depuradores de Clase E/metabolismo , Sirolimus/administración & dosificación , Trombomodulina/metabolismo , Vasodilatadores/farmacologíaRESUMEN
PURPOSE: Monocytes (Mon1-2-3) play a substantial role in low-grade inflammation associated with high cardiovascular morbidity and mortality of patients with chronic kidney disease (CKD) and chronic heart failure (CHF). The effect of an acute exercise bout on monocyte subsets in the setting of systemic inflammation is currently unknown. This study aims (1) to evaluate baseline distribution of monocyte subsets in CHF and CKD versus healthy subjects (HS) and (2) to evaluate the effect of an acute exercise bout. Exercise-induced IL-6 and MCP-1 release are related to the Mon1-2-3 response. METHODS: Twenty CHF patients, 20 CKD patients, and 15 HS were included. Before and after a maximal cardiopulmonary exercise test, monocyte subsets were quantified by flow cytometry: CD14(++)CD16(-)CCR2(+) (Mon1), CD14(++)CD16(+)CCR2(+) (Mon2), and CD14(+)CD16(++)CCR2(-) (Mon3). Serum levels of IL-6 and MCP-1 were determined by ELISA. RESULTS: Baseline distribution of Mon1-2-3 was comparable between the 3 groups. Following acute exercise, %Mon2 and %Mon3 increased significantly at the expense of a decrease in %Mon1 in HS and in CKD. This response was significantly attenuated in CHF (P < 0.05). In HS only, MCP-1 levels increased following exercise; IL-6 levels were unchanged. Circulatory power was a strong and independent predictor of the changes in Mon1 (ß = -0.461, P < 0.001) and Mon3 (ß = 0.449, P < 0.001); and baseline LVEF of the change in Mon2 (ß = 0.441, P < 0.001). CONCLUSION: The response of monocytes to acute exercise is characterized by an increase in proangiogenic and proinflammatory Mon2 and Mon3 at the expense of phagocytic Mon1. This exercise-induced monocyte subset response is mainly driven by hemodynamic changes and not by preexistent low-grade inflammation.
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Ejercicio Físico , Insuficiencia Cardíaca/sangre , Fallo Renal Crónico/sangre , Monocitos/citología , Adulto , Índice de Masa Corporal , Quimiocina CCL2/sangre , Prueba de Esfuerzo , Femenino , Citometría de Flujo , Tasa de Filtración Glomerular , Voluntarios Sanos , Humanos , Inflamación , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Neovascularización FisiológicaRESUMEN
Stents have become a standard of care for the treatment of coronary artery disease. A series of cellular and molecular processes contribute to the vascular response following stent placement. For the purpose of local gene expression studies, metallic stent struts are usually removed from the vessel wall with forceps under a dissection microscope prior to RNA extraction. Main drawbacks of the manual dissection are that it may cause additional tissue damage and compromise the quality of RNA through prolonged tissue handling. In this technical note, we report the recovery of high-quality RNA from atherosclerotic vessels with stent struts left in situ.
Asunto(s)
Aterosclerosis/metabolismo , Vasos Coronarios/fisiología , ARN/aislamiento & purificación , Stents , Animales , Aterosclerosis/terapia , Stents Liberadores de Fármacos , Perfilación de la Expresión Génica/métodos , Masculino , Metales , ARN/análisis , ARN Ribosómico 18S/análisis , ARN Ribosómico 18S/aislamiento & purificación , ARN Ribosómico 28S/análisis , ARN Ribosómico 28S/aislamiento & purificación , ConejosRESUMEN
AIM: To evaluate differences in strut coverage, inflammation and endothelialization between two second-generation polymer-based drug-eluting stents (DES) in an atherosclerotic rabbit double-injury iliac artery model at 28 days follow-up. METHODS AND RESULTS: Rabbits with induced atheroma received bilateral iliac artery stents: everolimus-eluting stent (Xience V EES; Abbott Vascular), zotarolimus-eluting stent (Resolute ZES; Medtronic CardioVascular), or bare-metal stent (BMS; MultiLink Vision; Abbott Vascular). After 28 days, total neointimal coverage examined by scanning electron microscopy was >98% for all three stent types. Neointimal thickness above stent struts was decreased by 50% in Xience V EES (0.06 ± 0.01 mm; P = 0.00001) compared with BMS (0.15 ± 0.03 mm) and Resolute ZES (0.12 ± 0.04 mm). Luminal area was largest for Xience V EES (3.79 ± 0.33 mm(2) ; P = 0.0003 for Xience V EES vs. BMS), followed by Resolute ZES (3.46 ± 0.45 mm(2) ; P = 0.083 for Resolute ZES vs. BMS) and BMS (3.07 ± 0.53 mm(2) ). Percentage area stenosis was smallest for Xience V EES (17.23 ± 3.64%; P = 0.00001), while BMS (30.25 ± 7.48%) and Resolute ZES (30.79 ± 7.15%) did not differ. Endothelial monolayer regrowth was significantly lower in Resolute ZES (65 ± 13%) versus BMS (79 ± 11%; P = 0.004). There was no difference between Xience V EES (74 ± 10%) and BMS. Xience V EES was further associated with a lower number of inflammatory cells surrounding the stent struts (7 ± 2 per strut) in comparison to Resolute ZES (15 ± 6; P = 0.0001) and BMS (17 ± 9; P = 0.0005). CONCLUSION: In this atherosclerotic rabbit model, Xience V EES suppressed neointimal thickening better, with normal endothelial regrowth as compared with BMS, and less strut-induced inflammation.
Asunto(s)
Angioplastia de Balón/instrumentación , Aterosclerosis/terapia , Stents Liberadores de Fármacos , Arteria Ilíaca/lesiones , Lesiones del Sistema Vascular/terapia , Angioplastia de Balón/efectos adversos , Animales , Aterosclerosis/diagnóstico por imagen , Aterosclerosis/patología , Fármacos Cardiovasculares/administración & dosificación , Proliferación Celular , Modelos Animales de Enfermedad , Células Endoteliales/ultraestructura , Everolimus , Arteria Ilíaca/diagnóstico por imagen , Arteria Ilíaca/ultraestructura , Inflamación/etiología , Inflamación/patología , Inflamación/prevención & control , Masculino , Neointima , Diseño de Prótesis , Conejos , Radiografía , Sirolimus/administración & dosificación , Sirolimus/análogos & derivados , Factores de Tiempo , Lesiones del Sistema Vascular/diagnóstico por imagen , Lesiones del Sistema Vascular/patologíaRESUMEN
Compared to bare metal stent angioplasty, first-generation drug-eluting stents (DES) have markedly reduced the incidence of in-stent restenosis. However, given the increased concerns over late and very late stent thrombosis, newer-generation DES were developed. To date, these DES have virtually replaced the use of first-generation DES worldwide. In this review article, we carefully consider the pre-clinical and clinical trials that have been performed with currently available, european conformity-marked and Food and Drug Administration-approved new-generation Resolute(®) and Xience V(®) DES.
Asunto(s)
Angioplastia Coronaria con Balón/métodos , Implantación de Prótesis Vascular , Enfermedad de la Arteria Coronaria/terapia , Stents Liberadores de Fármacos , Inmunosupresores/uso terapéutico , Sirolimus/análogos & derivados , Angioplastia Coronaria con Balón/efectos adversos , Everolimus , Oclusión de Injerto Vascular/prevención & control , Humanos , Inmunosupresores/efectos adversos , Sirolimus/efectos adversos , Sirolimus/uso terapéutico , Resultado del TratamientoRESUMEN
Endothelial progenitor cells (EPC) and angiogenic T cells have not been validated for use in studies that involve delayed sample processing and analysis. Here, we report our results for the flow cytometric enumeration of circulating EPC and angiogenic T cells using TransFix®-treated whole blood obtained from adult patients with cardiovascular disease and healthy volunteers. Both cell types promote neovascularization and vascular homeostasis. As such they have been put forward as novel diagnostic markers for endothelial dysfunction and may add prognostic information in patients with cardiovascular disease. Our findings indicate that by the addition of TransFix® cellular antigen stabilizing reagent to whole blood, analyses can be postponed up to 7 days after blood collection. Therefore, this procedure may facilitate laboratory workflow, as well as the organization of multicenter studies, which requires analyses to be conducted in a central core laboratory.
Asunto(s)
Células Endoteliales/citología , Citometría de Flujo/instrumentación , Citometría de Flujo/métodos , Neovascularización Fisiológica , Células Madre/citología , Linfocitos T/citología , Adulto , Anciano , Antígenos/metabolismo , Antígenos CD34/biosíntesis , Complejo CD3/biosíntesis , Separación Celular , Ejercicio Físico , Homeostasis , Humanos , Persona de Mediana EdadRESUMEN
Exercise training improves endothelial function in patients with chronic heart failure (CHF) through functional enhancement of circulating angiogenic cells and increased numbers of circulating endothelial progenitor cells (EPC). In contrast to healthy subjects, an immediate effect of acute exercise on CD34(+)/KDR(+) EPC is absent in CHF. Whether this reflects an attenuated or rather delayed mobilization, is addressed in the present study by measuring CD34(+)/KDR(+) EPC over a longer time period post-exercise. Seven CHF patients and eight healthy subjects (HS; 4 young and 4 age-matched subjects) underwent graded exercise testing (GXT). Venous blood was sampled before and 10, 30, and 60 min, 2, 4, 8, 12, 24 and 48 h following GXT to determine numbers of circulating CD34(+)/KDR(+) EPC (flow cytometry) and serum levels of stromal cell-derived factor (SDF)-1α (ELISA). In both HS groups, CD34(+)/KDR(+) EPC numbers increased within 10 min following GXT and remained elevated for up to 2 h. In CHF patients, the initial increase was small and normalized within 30 min. Evolution of CD34(+)/KDR(+) EPC numbers over time following GXT overall was attenuated in CHF versus HS (p = 0.036). Exercise considerably influenced SDF-1α levels over time (p = 0.0008), without a relation to the changes in CD34(+)/KDR(+) EPC. The immediate effect of acute exercise on CD34(+)/KDR(+) EPC numbers is not delayed, but significantly attenuated in CHF patients compared to HS.
Asunto(s)
Células Endoteliales/fisiología , Ejercicio Físico/fisiología , Insuficiencia Cardíaca/patología , Células Madre/fisiología , Adulto , Anciano , Enfermedad Crónica , Células Endoteliales/patología , Prueba de Esfuerzo , Femenino , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Esfuerzo Físico/fisiología , Células Madre/patología , Factores de Tiempo , Adulto JovenRESUMEN
AIMS: Recruitment of endothelial progenitor cells (EPCs) and enhanced activity of circulating angiogenic cells (CACs) might explain the benefits of exercise training in reversing endothelial dysfunction in chronic heart failure (CHF) patients. We studied baseline EPC numbers and CAC function and the effect of a single exercise bout. METHODS AND RESULTS: Forty-one CHF patients (mild, n = 22; severe, n = 19) and 13 healthy subjects were included. Migratory activity of CACs was evaluated in vitro and circulating CD34+ and CD34+/KDR+ (EPC) cells were quantified by flow cytometry before and after cardiopulmonary exercise testing (CPET). Circulating stromal cell-derived factor-1alpha (SDF-1alpha) and vascular endothelial growth factor (VEGF) concentrations were measured. Both CAC migration as well as CD34+ cell numbers were significantly reduced in CHF, whereas CD34+/KDR+ cells were not different from controls. Endothelial dysfunction was related to impaired CAC migration (r = 0.318, P = 0.023). Cardiopulmonary exercise testing improved CAC migration in severe (+52%, P < 0.005) and mild CHF (+31%, P < 0.005), restoring it to levels similar to controls. Following CPET, SDF-1alpha increased in healthy controls and mild CHF (P < 0.005). Vascular endothelial growth factor, CD34+, and CD34+/KDR+ cell numbers remained unchanged. CONCLUSION: The present findings reveal a potent stimulus of acute exercise to reverse CAC dysfunction in CHF patients with endothelial dysfunction.