RESUMEN
BACKGROUND: In this study we sought to examine whether transcatheter aortic valve implantation (TAVI) is followed by a change in the plasma levels of novel cardiovascular biomarkers. METHODS: We collected blood samples of 79 patients with severe aortic valve stenosis undergoing TAVI before and at 7 days, 1 month, 3 months and 6 months post TAVI and analyzed the plasma concentrations of GDF-15, H-FABP, fetuin-A, galectin 3, sST2 and suPAR by means of ELISA. RESULTS: There was a significant increase in the concentration of fetuin-A (median: 52.44 mg/ml to 113.2 mg/ml, p < 0.001) and a significant decrease of H-FABP after TAVI (median: 4.835 ng/ml to 2.534 ng/ml, p < 0.001). The concentrations of suPAR and sST2 showed an initial increase (suPAR median: 2755 pg/ml 3489 pg/ml, p < 0.001; sST2 median: 5832 pg/ml to 7137 pq/ml, p < 0.001) and subsequently decreased significantly. CONCLUSION: We hypothesize that the decrease of H-FABP and the increase of fetuin-A could be due to a hemodynamic improvement after valve replacement. The initial increase of suPAR could indicate an inflammatory stimulus and the significant increase in sST2 could be due to the mechanical strain caused by implantation of the valve.
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Biomarcadores/sangre , Periodo Posoperatorio , Reemplazo de la Válvula Aórtica Transcatéter , Anciano , Anciano de 80 o más Años , Estenosis de la Válvula Aórtica/sangre , Estenosis de la Válvula Aórtica/cirugía , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/diagnóstico , Proteína 3 de Unión a Ácidos Grasos/sangre , Hemodinámica , Humanos , Proteína 1 Similar al Receptor de Interleucina-1/sangre , Proteínas de la Membrana/sangre , Proteínas de Neoplasias/sangre , Factores de Tiempo , alfa-2-Glicoproteína-HS/análisisRESUMEN
BACKGROUND: Soluble ST2 (sST2) has been introduced as a novel biomarker in patients suffering from heart failure for risk stratification. In this study, we sought to investigate whether sST2 is useful for risk stratification and prediction of mortality in patients undergoing transcatheter aortic valve implantation (TAVI). MATERIALS AND METHODS: A total of 274 patients undergoing TAVI were included in this study (149 female; age 81 ± 1 years; EUROSCORE 25 ± 1; STS score 3·8 ± 0·2). Plasma samples were obtained preinterventional and analysed for sST2. Patients were followed up 1 month and 1 year after TAVI. RESULTS: In a Cox regression analysis, sST2 plasma concentration was associated with increased mortality (changes per pg/mL sST2 concentration; HR 1·00006 95% (1·00004-1·00009); P < 0·001). A cut-off by means of the Youden Index was calculated (10 070·27 pg/mL), and patients were retrospectively divided into two cohorts, in those above (31·3%) and those below (68·7%) this value. These two groups were then compared regarding mortality both after 30 days and 1 year: whereas 1-month mortality did not differ (7·0% vs. 10·3%, OR 1·50 95% CI (0·60-3·79; P = 0·46)), patients with a sST2 concentration above the cut-off of 10 070·27 pg/mL showed a significantly worse outcome after 1 year (49·2% vs. 23·2%; OR 3·21 95% CI (1·70-6·04); P < 0·001). After correction for confounders in a multivariate Cox regression analysis, sST2 (1·0002 95% CI (1·0001-1·0003); P = 0·001) concentration remained associated with mortality. CONCLUSIONS: sST2 levels were associated with 1-year mortality after TAVI. Based on these results, we assume that sST2 might help to identify patients at high risk for death in whom conservative treatment should be considered.
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Estenosis de la Válvula Aórtica/cirugía , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Reemplazo de la Válvula Aórtica Transcatéter/mortalidad , Estenosis de la Válvula Aórtica/sangre , Estenosis de la Válvula Aórtica/mortalidad , Estudios de Cohortes , Femenino , Humanos , Masculino , Volumen Sistólico/fisiología , Resultado del TratamientoRESUMEN
BACKGROUND: Novel biomarkers representing different pathobiological pathways and their role in patients with acute myocardial infarction (AMI) were studied. METHODS: We retrospectively analysed serum levels of soluble suppression of tumorigenicity (sST2), growth-differentiation factor-15 (GDF-15), soluble urokinase plasminogen activator receptor (suPAR), heart-type fatty acid-binding protein (H-FABP) and plasma fetuin A in blood of patients with AMI (STEMI, n = 61; NSTEMI, n = 57) compared to controls with excluded coronary artery disease (n = 76). Furthermore, detailed correlation analysis was performed. RESULTS: Compared with controls, in patients with STEMI and NSTEMI higher levels expressed as median of sST2 in pg/mL (STEMI: 13210·9, NSTEMI: 11989·1, control: 5248; P < 0·001), GDF-15 in pg/mL (STEMI: 818·8, NSTEMI 677·5, control 548·6; P < 0·001), suPAR in pg/mL (STEMI: 3461·1, NSTEMI: 3466·7, control: 2463·6; P < 0·001), H-FABP in ng/mL (STEMI: 5·8, NSTEMI: 5·4, control: 0·0; P < 0·001) and lower plasma fetuin A levels in µg/mL (STEMI: 95, NSTEMI: 54, control: 116·6; P < 0·001) were detected. Correlation analysis found clinical and biochemical parameters such as ejection fraction, length of hospital stay, creatine kinase, NT-proBNP and hs Troponin T levels as well as inflammatory markers (CRP, leucocytes) to be significantly correlated with novel biomarkers. CONCLUSION: Plasma levels of novel biomarkers were significantly elevated (sST2, GDF-15, H-FABP, suPAR) or inversely downregulated (fetuin A) in patients with AMI compared to a control group with excluded coronary artery disease. Significant correlations with various clinical parameters and standard biochemical markers were found.
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Proteína 3 de Unión a Ácidos Grasos/sangre , Factor 15 de Diferenciación de Crecimiento/sangre , Proteína 1 Similar al Receptor de Interleucina-1/sangre , Infarto del Miocardio/sangre , Receptores del Activador de Plasminógeno Tipo Uroquinasa/sangre , alfa-2-Glicoproteína-HS/metabolismo , Anciano , Biomarcadores/sangre , Biomarcadores/metabolismo , Proteína C-Reactiva/inmunología , Estudios de Casos y Controles , Creatina Quinasa/sangre , Femenino , Humanos , Tiempo de Internación , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/inmunología , Infarto del Miocardio/metabolismo , Péptido Natriurético Encefálico/sangre , Infarto del Miocardio sin Elevación del ST/sangre , Infarto del Miocardio sin Elevación del ST/metabolismo , Fragmentos de Péptidos/sangre , Infarto del Miocardio con Elevación del ST/sangre , Infarto del Miocardio con Elevación del ST/metabolismo , Volumen Sistólico , Troponina T/sangreRESUMEN
BACKGROUND: Obesity represents a major problem for patients and health care systems in most industrialized countries. A chronic inflammatory state in obese individuals leads to disease conditions associated with activation of cellular immune mechanisms. Here, we sought to investigate the role of Th1-, Th2-, and Th17-related cytokines in overweight adolescents and mice on a high-fat diet. METHODS: Plasma samples were obtained from 79 male adolescents aged 13-17 years. Thirty-seven of them had a body mass index (BMI) above the 90th age-specific percentile. Th1, Th2, and Th17 cytokines were measured using Bio-Plex multiplex technology (Bio-Rad, Hercules, USA). In an experimental approach, mice were fed with high-fat (HFD) or normal chow for 15 weeks. RESULTS: Interleukin (IL)-17 concentrations were significantly decreased in overweight adolescents compared to lean controls [99.8 ± 7.3 pg/mL standard error of the mean (SEM) vs 146.6 ± 11.5 pg/mL SEM P = .001]. Levels of IL-17 correlated significantly with anthropometrical parameters of obesity. A concordant response was found in mice consuming a HFD for 15 weeks compared to controls (861 ± 165 pg/mL SEM vs 1575 ± 187 pg/ml SEM, P = .0183). However, a biphasic response was evident for most Th1, Th2, and Th17 cytokines as levels initially increased within the first 5 weeks on HFD and showed a decline afterwards. CONCLUSIONS: In contrast to previous studies showing elevated levels of IL-17 in obese adults, we found a decreasing trend in overweight adolescents. This difference could possibly be related to the fact that disease conditions associated with obesity such as hypertension, vascular pathologies, diabetes, and a triggering of the Th1/Th17 axis were not yet present in overweight teenagers.
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Citocinas/sangre , Obesidad/sangre , Linfocitos T Colaboradores-Inductores/metabolismo , Adolescente , Animales , Citocinas/metabolismo , Humanos , Masculino , Ratones Endogámicos C57BL , Obesidad/inmunologíaRESUMEN
BACKGROUND: Endothelial progenitor cells (EPC) are involved in neovascularization and endothelial integrity. They might be protective in atherosclerosis. Optical coherence tomography (OCT) is a precise intracoronary imaging modality that allows assessment of subintimal plaque development. We evaluated the influence of EPC on coronary plaque burden in stable disease and implemented a novel computational plaque analysis algorithm using OCT. METHODS: Forty-three patients (69.8% males, 69.6 ± 7.7 years) were investigated by OCT during re-angiography 6 months after elective stent implantation. Different subpopulations of EPCs were identified by flow cytometry according to their co-expression of antigens (CD34+, CD133+, kinase domain receptor, KDR+). An algorithm was applied to calculate the underlying total plaque burden of the stented segments from OCT images. Plaque morphology was assessed according to international consensus in OCT imaging. RESULTS: A cumulative sub-strut plaque volume of 10.87 ± 12.7 mm3 and a sub-stent plaque area of 16.23 ± 17.0 mm2 were found within the stented vessel segments with no significant differences between different stent types. All EPC subpopulations (mean of EPC levels: CD34+/CD133+: 2.66 ± 2.0%; CD34+/KDR+: 7.50 ± 5.0%; CD34+/CD133+/KDR+: 1.12 ± 1.0%) inversely correlated with the identified underlying total plaque volume and plaque area (p ≤ 0.012). CONCLUSIONS: This novel analysis algorithm allows for the first time comprehensive quantification of coronary plaque burden by OCT and illustration as spread out vessel charts. Increased EPC levels are associated with less sub-stent coronary plaque burden which adds to previous findings of their protective role in atherosclerosis.
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Reestenosis Coronaria/diagnóstico , Procedimientos Quirúrgicos Electivos/efectos adversos , Células Progenitoras Endoteliales/patología , Intervención Coronaria Percutánea/efectos adversos , Placa Aterosclerótica/diagnóstico , Stents/efectos adversos , Tomografía de Coherencia Óptica/métodos , Anciano , Algoritmos , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/cirugía , Reestenosis Coronaria/etiología , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/cirugía , Femenino , Citometría de Flujo , Estudios de Seguimiento , Humanos , Masculino , Placa Aterosclerótica/cirugía , Pronóstico , Falla de Prótesis , Reproducibilidad de los Resultados , Factores de TiempoRESUMEN
BACKGROUND: The induction of microvascular inflammation and the effects on cytokine production in blood due to hypoxia has been shown in the past. We have previously reported a statistically significant increase of the pro-inflammatory cytokine interleukin-8 (IL-8) in normobaric hypoxia in the setting of a hypoxia-chamber. In the present study, we sought to analyze plasma levels of inflammatory cytokines in a real-life stetting in order to foster our knowledge on hypoxia induced microvascular inflammation at moderate altitude. METHODS: Pro-inflammatory cytokines (IL-8, IL-6, TNF-α) were measured in an experimental field study, exposing 18 healthy volunteers to moderate hypoxia while staying at a mountain lodge in Diavolezza, Switzerland (2978 meters above sea level). Plasma cytokine levels were measured by ELISA. RESULTS: In contradiction to our results in a normobaric hypoxia-chamber, exposure to moderate hypoxia led to a significant decrease of plasma IL-8 levels in a real-life setting (from 2.902 (1.046 - 4.984) pg/mL to 1.395 (0.698 - 3.712) pg/mL, p = 0.034). Concentrations of IL-6 and TNF-α did not show statistically significant changes in comparison to baseline measurements. CONCLUSIONS: The results of this study show a decrease of proinflammatory cytokine IL-8 in a real life setting of moderate altitude in healthy individuals. Initiation of angiogenesis or subliminal stimulus for an altitude-induced inflammatory reaction may be explanations for this unexpected finding.
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Altitud , Citocinas/metabolismo , Adulto , Voluntarios Sanos , Humanos , Hipoxia , Interleucina-6 , Interleucina-8/metabolismo , Factor de Necrosis Tumoral alfaRESUMEN
Early detection of atherosclerosis, i.e., in occupational health screening programs could reduce the rate of cardiovascular events in the working population. Changes of the augmentation index (AIX) correlate with changes of the arterial stiffness induced by aging, atherosclerosis, or arterial hypertension and have a prognostic value for cardiovascular events. Their diagnostic yield should be increased by normalizing the AIX to age, in terms of a calculating the vascular age (VA). In this pilot study, 30 patients (mean age 65.3 ± 8.8 years, 21 male) with suspected coronary heart disease underwent a duplex ultrasound of the carotid arteries and a measurement of the ankle brachial index in addition to the coronary angiography. The AIX was recorded with a portable device (Vascular Explorer), and the VA was calculated. Atherosclerosis was found in 24 patients. They were older than the patients without atherosclerosis, but there was no age dependency found for the distribution pattern or severity of atherosclerosis. In patients with findings of atherosclerosis, the calculated VA was higher than the chronological age, and these differences were significant in patients below 65 years of age. Comparing patients in higher blood pressure classes with patients in lower classes, significantly higher AIX, VA, and differences to the chronological age were found. The VA, deduced from the noninvasively obtained AIX, is a promising candidate for screening programs for atherosclerosis, i.e., in occupational health screening programs.
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Envejecimiento , Aterosclerosis/diagnóstico , Aterosclerosis/fisiopatología , Arterias Carótidas/diagnóstico por imagen , Anciano , Índice Tobillo Braquial , Angiografía Coronaria , Femenino , Humanos , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Proyectos Piloto , Valor Predictivo de las Pruebas , Ultrasonografía Doppler Dúplex , Rigidez VascularRESUMEN
Degenerative aortic stenosis (AS) is the most frequent form of acquired valvular heart disease. AS is known to entail endothelial dysfunction caused by increased mechanical shear stress leading to elevated circulatory levels of microparticles. Endothelial and platelet microparticles (EMP and PMP) are small vesicles that originate from activated cells and thrombocytes. We sought to evaluate whether transcatheter aortic valve implantation (TAVI) procedure would elicit effects on circulating EMP and PMP. 92 patients undergoing TAVI procedure for severe AS were included in this study. Samples were obtained at each visit before TAVI, 1 week post-procedure and at 1, 3 and after 6 months after TAVI and were evaluated using flow cytometry. A 12 month clinical follow-up was also performed. CD62E+ EMP concentration before TAVI was 21.11 % (±6.6 % SD) and declined to 20.99 % (±6.8 % SD) after 1 week, to 16.63 % (±5.4 % SD, p < 0.0001) after 1 month, to 17.08 % (±4.6 % SD, p < 0.0001) after 3 months and to 15.94 % (±5.4 % SD, p < 0.0001) after 6 months. CD31+/CD42b-, CD31+/Annexin+/- EMP remained unchanged. CD31+/CD41b+ PMP evidenced a slight, but statistically significant increase after TAVI and remained elevated during the entire follow-up. Apart from a procedure-related improvement in echocardiographic parameters, TAVI procedure led also to a decline in CD62E+ EMP. The reduction in pressure gradients with less hemodynamic shear stress seems also to have beneficially affected endothelial homeostasis.
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Estenosis de la Válvula Aórtica/cirugía , Biomarcadores/metabolismo , Plaquetas/metabolismo , Micropartículas Derivadas de Células/metabolismo , Células Endoteliales/metabolismo , Reemplazo de la Válvula Aórtica Transcatéter , Anciano , Anciano de 80 o más Años , Válvula Aórtica/cirugía , Ecocardiografía , Femenino , Citometría de Flujo , Alemania , Hemodinámica , Humanos , Masculino , Activación Plaquetaria , Factores de Tiempo , Resultado del TratamientoRESUMEN
The transcatheter valve technology pipeline has started as simple balloon valvuloplasty for the treatment of stenotic heart valves and evolved since the year 2000 to either repair or replace heart valves percutaneously with multiple devices. In this review, the present technology and its application are illuminated and a glimpse into the near future is dared from a physician's perspective.
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Enfermedades de las Válvulas Cardíacas , Adulto , Valvuloplastia con Balón , Cateterismo Cardíaco , Implantación de Prótesis de Válvulas Cardíacas , HumanosRESUMEN
The impact of reactive oxygen species and phosphoinositide 3-kinase (PI3K) in differentiating embryonic stem (ES) cells is largely unknown. Here, we show that the silencing of the PI3K catalytic subunit p110α and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 (NOX1) by short hairpin RNA or pharmacological inhibition of NOX and ras-related C3 botulinum toxin substrate 1 (Rac1) abolishes superoxide production by vascular endothelial growth factor (VEGF) in mouse ES cells and in ES-cell-derived fetal liver kinase-1(+) (Flk-1(+)) vascular progenitor cells, whereas the mitochondrial complex I inhibitor rotenone does not have an effect. Silencing p110α or inhibiting Rac1 arrests vasculogenesis at initial stages in embryoid bodies, even under VEGF treatment, as indicated by platelet endothelial cell adhesion molecule-1 (PECAM-1)-positive areas and branching points. In the absence of p110α, tube-like structure formation on matrigel and cell migration of Flk-1(+) cells in scratch migration assays are totally impaired. Silencing NOX1 causes a reduction in PECAM-1-positive areas, branching points, cell migration and tube length upon VEGF treatment, despite the expression of vascular differentiation markers. Interestingly, silencing p110α but not NOX1 inhibits the activation of Rac1, Ras homologue gene family member A (RhoA) and Akt leading to the abrogation of VEGF-induced lamellipodia structure formation. Thus, our data demonstrate that the PI3K p110α-Akt/Rac1 and NOX1 signalling pathways play a pivotal role in VEGF-induced vascular differentiation and cell migration. Rac1, RhoA and Akt phosphorylation occur downstream of PI3K and upstream of NOX1 underscoring a role of PI3K p110α in the regulation of cell polarity and migration.
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Diferenciación Celular/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Células Madre Embrionarias de Ratones/enzimología , NADH NADPH Oxidorreductasas/metabolismo , Neovascularización Fisiológica/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/farmacología , Animales , Diferenciación Celular/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Ratones , Células Madre Embrionarias de Ratones/citología , NADH NADPH Oxidorreductasas/genética , NADPH Oxidasa 1 , Neovascularización Fisiológica/genética , Transducción de Señal/genética , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Increased levels of endothelial cell microparticles (EMP) are known to reflect endothelial dysfunction (ED). In diabetes mellitus type 2 (T2DM), the expression of endothelin (ET)-1 is increased. As treatment with an ET-1 antagonist significantly inhibited atherosclerosis in animal models, we sought to investigate whether treatment with ET-1 antagonists affects EMP levels in vitro and in vivo in patients with T2DM. MATERIALS AND METHODS: In vitro study: Human umbilical vein endothelial cells (HUVEC) were stimulated with ET-1 alone and ET-1 in combination with a dual ET-A and ET-B endothelin receptor blocker. In vivo study: Patients with T2DM were randomized to treatment with the ET receptor antagonist bosentan or placebo. After 4 weeks, the patients were re-examined and blood samples were obtained. EMP counts in supernatants and plasma samples were determined using flow cytometry. RESULTS: In vitro study: In supernatants of ET-1-stimulated HUVECs, the increased release of EMP was reduced significantly by co-incubation with an ET-1 receptor antagonist (e.g. CD31+/CD42b-EMP decreased from 37·1% ± 2·8 to 31·5% ± 2·8 SEM, P = 0·0078). In vivo study: No changes in EMP levels in blood samples of patients with T2DM were found after 4 weeks of bosentan treatment (n = 36, P = ns). CONCLUSIONS: Our in vitro results suggest that ET-1 stimulates the release of EMP from HUVECs via a receptor-dependent mechanism. Co-incubation with an endothelin receptor blocker abolished ET-1-dependent EMP release. However, treatment with bosentan for 4 weeks failed to alter EMP levels in patients with T2DM. Other factors seem to have influenced EMP release in patients with T2DM independent of ET-1 receptor-mediated mechanisms.
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Micropartículas Derivadas de Células/efectos de los fármacos , Antagonistas de los Receptores de la Endotelina A/farmacología , Receptor de Endotelina A/fisiología , Bosentán , Diabetes Mellitus Tipo 2/metabolismo , Método Doble Ciego , Antagonistas de los Receptores de Endotelina/uso terapéutico , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Persona de Mediana Edad , Sulfonamidas/farmacologíaRESUMEN
BACKGROUND: During exposure to high altitude, the immune system is altered. During hypoxia, an increase in interleukin (IL)-6 and high sensitivity C-reactive protein (hs-CRP), and an increase in natural killer cells and decrease in T cells in blood was shown. However, the impact of hypoxia on dendritic cells has not been investigated yet. MATERIAL AND METHODS: Twelve healthy volunteers were subjected to a transient normobaric hypoxia for 6·5 h simulating an oxygen concentration at 5500 m. During exposure to hypoxia, blood samples were collected and analysed by flow cytometrical cell sorting (FACS) for circulating myeloid (mDCs) and plasmacytoid (pDCs) DCs. Serum levels of IL-6 and tumour necrosis factor (TNF)-α were analysed. In a cell culture hypoxia chamber, blood samples were subjected to the same hypoxia and analysed regarding DCs. RESULTS: Exposure to normobaric hypoxia induced a significant decrease in circulating pDCs about 45% (P = 0·001) but not of mDC compared to baseline normoxia. Furthermore, we observed a significant increase of TNF-α about 340% (P = 0·03) and of IL-6 about 286% (P = 0·002). In cell culture experiments exposure of blood to hypoxia led to no significant changes in DCs, so that a direct cytotoxic effect was excluded. During hypoxia, we observed a transient increase in stromal-derived factor 1 (SDF-1) which is important for pDC tissue recruitment. CONCLUSIONS: We show a significant decrease in circulating pDCs during hypoxia in parallel to a pro-inflammatory response. Further studies are necessary to evaluate whether the decrease in circulating pDCs might be the result of an enhanced tissue recruitment.
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Presión Atmosférica , Células Dendríticas/inmunología , Hipoxia/inmunología , Interleucina-6/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Adulto , Altitud , Recuento de Células , Células Dendríticas/citología , Femenino , Citometría de Flujo , Voluntarios Sanos , Frecuencia Cardíaca , Humanos , Hipoxia/sangre , Ácido Láctico/sangre , Masculino , Células Mieloides/citología , Células Mieloides/inmunología , Oximetría , Frecuencia RespiratoriaRESUMEN
AIMS: Immunity and inflammation processes are known to be of central importance in chronic heart failure (CHF). Dendritic cells (DCs) are key players in adaptive immunity, yet their role in CHF is still unknown. The aim of this study was to investigate the circulating DCs in patients with compensated CHF. METHODS: Circulating myeloid (m) and plasmacytoid (p) DCs, as well as inflammatory cytokines interleukine (IL) 6 and IL10 were flow cytometrically analysed in peripheral blood of clinically compensated CHF patients with previously diagnosed dilated cardiomyopathy (DCM, n = 69), ischaemic cardiomyopathy (ICM, n = 49), as well as in unaffected controls (n = 51). Correlation analysis was performed between circulating DCs, cytokines and parameters of heart failure severity, such as NYHA class, the marker brain natriuretic peptide (BNP) and echocardiographic parameters of left ventricular function and dilation. RESULTS: Circulating mDCs were significantly decreased in all CHF patients, although more pronounced in DCM (0.14%, P < 0.001) than in ICM (0.18%, P = 0.043) compared to controls (0.2%). In contrast, no statistical changes were observed for pDCs. Circulating mDCs correlated with left ventricular ejection fraction (LVEF) and inversely with LV end-diastolic diameter (LVEDd) in all CHF patients. For DCM patients, an inverse correlation of mDCs with BNP was additionally observed. Circulating mDCs correlated inversely with IL6 and IL10 in all CHF patients. With the exception of IL-6 and NYHA class of DCM patients, cytokines did not significantly correlate with heart failure parameters. CONCLUSIONS: Blood mDCs are decreased in CHF patients. The reduction correlates with the severity of their HF.
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Cardiomiopatía Dilatada/complicaciones , Citocinas/sangre , Células Dendríticas/inmunología , Insuficiencia Cardíaca , Isquemia Miocárdica/complicaciones , Inmunidad Adaptativa , Adulto , Anciano , Enfermedad Crónica , Femenino , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/inmunología , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Estadística como Asunto , Función Ventricular Izquierda/inmunologíaRESUMEN
BACKGROUND: Caval valve implantation has been suggested for transcatheter treatment of severe tricuspid regurgitation (TR). Combining the interventional technique with the promising surgical experience with decellularized valves, we sought to evaluate the functional and structural outcome of decellularized pericardial tissue valves (dTVs) in the low-pressure venous circulation in a chronic model of TR. METHODS AND RESULTS: Sixteen pericardial tissue valves were heterotopically implanted in the inferior and superior vena cava in a sheep model (54-98 kg; median 74.5 kg, n = 8) of severe TR. The devices were assembled using self-expanding nitinol stents and bovine pericardia decellularized by a detergent-based protocol (group dTV; n = 8). Glutaraldehyde-fixed pericardial tissue valves served as control (GaTV, n = 8). After 6 months, device function and structural maturation were analyzed using echocardiographic, histologic, immunohistologic, and electron microscopic approaches. After implantation, cardiac output increased significantly from 3.7 ± 1.1 l/min to 4.8 ± 1.1 l/min (P < 0.05) and competent valve function was verified by angiography. At 6 months, angiographic and echocardiographic evaluation revealed moderate to severe regurgitation in all GaTV. In contrast, five of the eight dTVs functioned well with only minor regurgitation. In these animals, autopsy revealed preserved valve structure with tender leaflets without signs of thrombosis or calcification. Conversely, GaTV showed severe degeneration with large calcification areas. Microscopic and histologic analysis confirmed endothelial repopulation in both valve types. However, additional interstitial reseeding was observed in decellularized valves. CONCLUSIONS: In the venous circulation in severe TR, decellularized valves show superior functional performance compared to Ga-fixed tissue valves. Macroscopic and microscopic analyses suggest preserved structural integrity and advanced endothelial and interstitial repopulation with evidence of less degradation in dTV. © 2014 Wiley Periodicals, Inc.
Asunto(s)
Bioprótesis , Cateterismo Cardíaco , Implantación de Prótesis de Válvulas Cardíacas , Prótesis Valvulares Cardíacas , Insuficiencia de la Válvula Tricúspide/terapia , Válvula Tricúspide , Vena Cava Inferior , Vena Cava Superior , Aleaciones , Animales , Cateterismo Cardíaco/efectos adversos , Cateterismo Cardíaco/instrumentación , Cateterismo Cardíaco/métodos , Enfermedad Crónica , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Implantación de Prótesis de Válvulas Cardíacas/instrumentación , Implantación de Prótesis de Válvulas Cardíacas/métodos , Hemodinámica , Diseño de Prótesis , Recuperación de la Función , Índice de Severidad de la Enfermedad , Ovinos , Stents , Factores de Tiempo , Válvula Tricúspide/diagnóstico por imagen , Válvula Tricúspide/metabolismo , Válvula Tricúspide/fisiopatología , Válvula Tricúspide/ultraestructura , Insuficiencia de la Válvula Tricúspide/diagnóstico , Insuficiencia de la Válvula Tricúspide/fisiopatología , UltrasonografíaRESUMEN
Purinergic signaling may be involved in embryonic development of the heart. In the present study, the effects of purinergic receptor stimulation on cardiomyogenesis of mouse embryonic stem (ES) cells were investigated. ADP or ATP increased the number of cardiac clusters and cardiac cells, as well as beating frequency. Cardiac-specific genes showed enhanced expression of α-MHC, MLC2v, α-actinin, connexin 45 (Cx45), and HCN4, on both gene and protein levels upon ADP/ATP treatment, indicating increased cardiomyogenesis and pacemaker cell differentiation. Real-time RT-PCR analysis of purinergic receptor expression demonstrated presence of P2X1, P2X4, P2X6, P2X7, P2Y1, P2Y2, P2Y4, and P2Y6 on differentiating ES cells. ATP and ADP as well as the P2X agonists ß,γ-methylenadenosine 5'-triphosphate (ß,γ-MetATP) and 8-bromoadenosine 5'-triphosphate (8-Br-ATP) but not UTP or UDP transiently increased the intracellular calcium concentration ([Ca(2+)](i)) as evaluated by the calcium indicator Fluo-4, whereas no changes in membrane potential were observed. [Ca(2+)](i) transients induced by ADP/ATP were abolished by the phospholipase C-ß (PLC-ß) inhibitor U-73122, suggesting involvement of metabotropic P2Y receptors. Furthermore, partial inhibition of [Ca(2+)](i) transients was achieved in presence of MRS2179, a selective P2Y1 receptor antagonist, whereas PPADS, a non-selective P2 receptor inhibitor, completely abolished the [Ca(2+)](i) response. Consequently, cardiomyocyte differentiation was decreased upon long term co-incubation of cells with ADP and P2 receptor antagonists. In summary, activation of purinoceptors and the subsequent [Ca(2+)](i) transients enhance the differentiation of ES cells toward cardiomyocytes. Purinergic receptor stimulation may be a promising strategy to drive the fate of pluripotent ES cells into a particular population of cardiomyocytes.
Asunto(s)
Adenosina Difosfato/farmacología , Adenosina Trifosfato/farmacología , Células Madre Embrionarias/efectos de los fármacos , Desarrollo de Músculos/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Adenosina Trifosfato/antagonistas & inhibidores , Animales , Calcio/metabolismo , Señalización del Calcio/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Femenino , Expresión Génica/efectos de los fármacos , Potenciales de la Membrana/efectos de los fármacos , Ratones , Contracción Miocárdica/efectos de los fármacos , Embarazo , Agonistas del Receptor Purinérgico P2X/farmacología , Antagonistas del Receptor Purinérgico P2Y/farmacología , Receptores Purinérgicos P2X/biosíntesis , Receptores Purinérgicos P2X/efectos de los fármacos , Receptores Purinérgicos P2X/genética , Receptores Purinérgicos P2Y1/efectos de los fármacos , Uridina Difosfato/farmacología , Uridina Trifosfato/farmacologíaRESUMEN
BACKGROUND: Increased markers of systemic inflammation had been found in patients with acute heart failure. These and other findings led to the hypothesis of an increased rate of bacterial translocation in severe or acute heart failure, leading to systemic inflammation. The present study examined if bacterial translocation occurs under physiological conditions in rats and if its rate and spectrum changes in chronic compensated ischemic heart failure. METHODS: Myocardial infarction (MI) was induced by proximal ligation of the left anterior descending coronary artery or a sham operation was performed. Rats were followed up for six months and mesenteric lymph nodes of the surviving animals with large MI were excised and bacterial translocation was quantified by cultivating viable bacteria. RESULTS: Induction of a large MI led to a significant cardiac remodelling, elevated levels of atrial natriuretic peptide, and pulmonary oedema. There was no difference in the spectrum or in the rate of bacterial translocation compared with controls, neither comparing all cultured bacteria nor predefined subgroups (e.g., intestinal bacteria). CONCLUSIONS: Bacterial translocation is a physiological process with no gradual increase in chronic compensated heart failure in rats.
Asunto(s)
Traslocación Bacteriana , Insuficiencia Cardíaca/microbiología , Mucosa Intestinal/fisiopatología , Isquemia Miocárdica/microbiología , Animales , Quimiocina CCL2/sangre , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/fisiopatología , Interleucina-6/sangre , Masculino , Isquemia Miocárdica/sangre , Isquemia Miocárdica/fisiopatología , Distribución Aleatoria , Ratas Endogámicas Lew , Remodelación VentricularRESUMEN
BACKGROUND: Hypoxia has been shown to induce a microvascular inflammation, affect the cell count of different types of immune cells, and influence cytokine production in blood. In the present study, serum levels of different cytokines were investigated to achieve insights into the effect of hypoxia on the balance of inflammation and anti-inflammation. METHODS: Pro- (IL-8) and anti-inflammatory (IL-10) cytokines were measured in an experiment exposing 12 healthy subjects (35 ± 9 yr, 176 ± 7 cm, 73 ± 16 kg, BMI 23 ± 4 kg/m2) to systemic, normobaric hypoxia in a hypoxic chamber. In this chamber oxygen was replaced by nitrogen to reach an oxygen content of 9.9% that is equivalent to an altitude of 5500 m during 7 hours. Serum cytokine concentrations were analyzed using ELISA. RESULTS: As expected, a significant decrease in peripheral oxygen saturation accompanied by a significant increase in breathing frequency and heart rate were observed in the subjects during hypoxia compared to baseline (BL). Blood leukocytes increased slightly, but significantly in the course of hypoxia. A statistically significant increase was measured for IL-8 serum level during hypoxia compared to the baseline measurements (BL 12.0 ± 1.1 pg/mL, hypoxia 16.2 ± 1.6 pg/mL, p = 0.006). For IL-10 a statistically significant decrease was measured upon hypoxia compared to baseline (BL 11.6 [6.2 - 43.31 pg/mL, hypoxia 8.3 [4.4 - 26.6] pg/mL, p = 0.016). Additionally, a significant inverse correlation was found comparing the anti-inflammatory cytokine IL-10 with the pro-inflammatory cytokine IL-8 (r = -0.69, p < 0.001). CONCLUSIONS: The results of this study demonstrate a hypoxia-induced increase in pro- and decrease in anti-inflammatory cytokines reflecting an increased pro-inflammatory status during hypoxia.
Asunto(s)
Hipoxia/complicaciones , Mediadores de Inflamación/sangre , Inflamación/etiología , Interleucina-10/sangre , Interleucina-8/sangre , Adulto , Biomarcadores/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Voluntarios Sanos , Humanos , Hipoxia/sangre , Hipoxia/inmunología , Inflamación/sangre , Inflamación/inmunología , Masculino , Factores de TiempoRESUMEN
Peripheral artery disease (PAD) is a common manifestation of atherosclerosis. Inflammation is important for initiation and progression of the disease. Dendritic cells (DCs) as antigen-presenting cells play an important role in the immune system. Therefore, we hypothesize that, in patients with PAD, DCPs might be reduced in blood due to their recruitment into the vascular wall and induce a proinflammatory response. The numbers of myeloid DCPs, plasmacytoid DCPs, and total DCPs were analyzed by flow cytometry in blood of patients with PAD (n = 52) compared to controls (n = 60). Femoralis plaques (n = 12) of patients who underwent surgery were immunostained for CD209 and CD83 (mDCs) as well as CD304, CD123 (pDCs), and HLA-DR. In patients with PAD, a significant decrease in mDCPs, pDCPs, and tDCPs was observed. In immunostaining, markers indicative for mDCs (CD209: 16 versus 8 cells/0.1 mm(2), P = 0.02; CD83: 19 versus 5 cells/0.1 mm(2), P = 0.03) were significantly elevated in femoralis plaques compared to control vessels. We show for the first time that mDCPs, pDCPs, and tDCPs are significantly reduced in patients with PAD. Immunohistochemical analysis unraveled that the decrease in DCPs might be due to their recruitment into atherosclerotic plaques.
Asunto(s)
Células Dendríticas/citología , Enfermedad Arterial Periférica/inmunología , Adulto , Anciano , Aterosclerosis/sangre , Estudios de Casos y Controles , Separación Celular , Ecocardiografía , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Inflamación/inmunología , Masculino , Persona de Mediana Edad , Células Mieloides/citología , Enfermedad Arterial Periférica/sangre , Placa Aterosclerótica/inmunologíaRESUMEN
Atherosclerosis is a chronic inflammatory disease of the arterial wall in which presentation of autoantigens by dendritic cells (DCs) leads to the activation of T cells. Anti-inflammatory cells like Tregs counterbalance inflammation in atherogenesis. In our study, human carotid plaque specimens were classified as stable (14) and unstable (15) according to established morphological criteria. Vessel specimens (n = 12) without any signs of atherosclerosis were used as controls. Immunohistochemical staining was performed to detect different types of DCs (S100, fascin, CD83, CD209, CD304, and CD123), proinflammatory T cells (CD3, CD4, CD8, and CD161), and anti-inflammatory Tregs (FoxP3). The following results were observed: in unstable lesions, significantly higher numbers of proinflammatory cells like DCs, T helper cells, cytotoxic T cells, and natural killer cells were detected compared to stable plaques. Additionally, there was a significantly higher expression of HLA-DR and more T cell activation (CD25, CD69) in unstable lesions. On the contrary, unstable lesions contained significantly lower numbers of Tregs. Furthermore, a significant inverse correlation between myeloid DCs and Tregs was shown. These data suggest an increased inflammatory state in vulnerable plaques resulting from an imbalance of the frequency of local pro- and anti-inflammatory immune cells.
Asunto(s)
Aterosclerosis/inmunología , Aterosclerosis/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Anciano , Antígenos CD/metabolismo , Proteínas Portadoras/metabolismo , Femenino , Factores de Transcripción Forkhead/metabolismo , Humanos , Células Asesinas Naturales/metabolismo , Activación de Linfocitos , Masculino , Proteínas de Microfilamentos/metabolismo , Persona de Mediana Edad , Linfocitos T Citotóxicos/metabolismo , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
BACKGROUND: Aortic stenosis is a frequent valvular disease especially in elderly patients. Catheter-based valve implantation has emerged as a valuable treatment approach for these patients being either at very high risk for conventional surgery or even deemed inoperable. The German Aortic Valve Registry (GARY) provides data on conventional and catheter-based aortic procedures on an all-comers basis. METHODS AND RESULTS: A total of 13 860 consecutive patients undergoing repair for aortic valve disease [conventional surgery and transvascular (TV) or transapical (TA) catheter-based techniques] have been enrolled in this registry during 2011 and baseline, procedural, and outcome data have been acquired. The registry summarizes the results of 6523 conventional aortic valve replacements without (AVR) and 3464 with concomitant coronary bypass surgery (AVR + CABG) as well as 2695 TV AVI and 1181 TA interventions (TA AVI). Patients undergoing catheter-based techniques were significantly older and had higher risk profiles. The stroke rate was low in all groups with 1.3% (AVR), 1.9% (AVR + CABG), 1.7% (TV AVI), and 2.3% (TA AVI). The in-hospital mortality was 2.1% (AVR) and 4.5% (AVR + CABG) for patients undergoing conventional surgery, and 5.1% (TV AVI) and AVI 7.7% (TA AVI). CONCLUSION: The in-hospital outcome results of this registry show that conventional surgery yields excellent results in all risk groups and that catheter-based aortic valve replacements is an alternative to conventional surgery in high risk and elderly patients.