RESUMEN
One factor that significantly contributes to renal allograft loss is chronic calcineurin inhibitor (CNI) nephrotoxicity (CIN). Among other factors, the complement (C-) system has been proposed to be involved CIN development. Hence, we investigated the impact of CNIs on intracellular signalling and the effects on the C-system in human renal tubule cells. In a qPCR array, CNI treatment upregulated C-factors and downregulated SOCS-3 and the complement inhibitors CD46 and CD55. Additionally, ERK1/-2 was required for these regulations. Following knock-down and overexpression of SOCS-3, we found that SOCS-3 inhibits ERK1/-2 signalling. Finally, we assessed terminal complement complex formation, cell viability and apoptosis. Terminal complement complex formation was induced by CNIs. Cell viability was significantly decreased, whereas apoptosis was increased. Both effects were reversed under complement component-depleted conditions. In vivo, increased ERK1/-2 phosphorylation and SOCS-3 downregulation were observed at the time of transplantation in renal allograft patients who developed a progressive decline of renal function in the follow-up compared to stable patients. The progressive cohort also had lower total C3 levels, suggesting higher complement activity at baseline. In conclusion, our data suggest that SOCS-3 inhibits CNI-induced ERK1/-2 signalling, thereby blunting the negative control of C-system activation.
Asunto(s)
Inhibidores de la Calcineurina/efectos adversos , Proteínas del Sistema Complemento/metabolismo , Ciclosporina/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/metabolismo , Rechazo de Injerto/metabolismo , Enfermedades Renales/metabolismo , Trasplante de Riñón , Túbulos Renales/efectos de los fármacos , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Tacrolimus/efectos adversos , Anciano , Anciano de 80 o más Años , Apoptosis , Antígenos CD55/metabolismo , Inhibidores de la Calcineurina/uso terapéutico , Línea Celular , Supervivencia Celular , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo , Ciclosporina/uso terapéutico , Femenino , Regulación de la Expresión Génica , Humanos , Enfermedades Renales/terapia , Túbulos Renales/patología , Sistema de Señalización de MAP Quinasas , Masculino , Proteína Cofactora de Membrana/metabolismo , Persona de Mediana Edad , Fosforilación , ARN Interferente Pequeño/genética , Proteína 3 Supresora de la Señalización de Citocinas/genética , Tacrolimus/uso terapéuticoRESUMEN
BACKGROUND: Persistent T-wave inversion (PTI) after ST-elevation myocardial infarction (STEMI) is associated with worse clinical outcome; however, the underlying mechanism between PTI and poor prognosis is incompletely understood. We sought to investigate the relationship between PTI and myocardial damage assessed by cardiac magnetic resonance (CMR) following STEMI. METHODS: In this prospective observational study, we included 142 consecutive revascularized STEMI patients. Electrocardiography to determine the presence and amplitude of PTI and pathological Q-waves was conducted 4months after infarction. CMR was performed within 1week after infarction and at 4months follow-up to evaluate infarct characteristics and myocardial function. RESULTS: Patients with PTI (n=103, 73%) showed a larger acute (21[11-29] vs. 6[1-13]%; p<0.001) and chronic infarct size (IS) (14[8-19] vs. 3[1-8]%; p<0.001) and more frequently microvascular obstruction (59 vs. 33%; p=0.02). The association between PTI and chronic IS remained significant (odds ratio: 9.02, 95%CI 3.49-23.35; p<0.001) after adjustment for pathological Q-wave and other IS estimators (high-sensitivity cardiac troponin T and C-reactive protein, N-terminal pro B-type natriuretic peptide, culprit vessel, pre-interventional TIMI flow). The value of PTI amplitude for the prediction of large chronic IS>11% (AUC: 0.84, 95%CI 0.77-0.90) was significantly higher compared to Q-wave amplitude (AUC: 0.72, 95%CI 0.63-0.80; p=0.009); the combination of PTI with pathological Q-wave (Q-wave/T-wave score) led to a net reclassification improvement of 0.43 (95% CI 0.29-0.57; p<0.001) as compared to PTI alone. CONCLUSIONS: PTI following STEMI is independently and incrementally associated with more extensive myocardial damage as visualized by CMR. An electrocardiographic score combining PTI with pathological Q-wave allows for a highly accurate IS estimation post-STEMI.
Asunto(s)
Electrocardiografía/tendencias , Imagen por Resonancia Cinemagnética/tendencias , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Infarto del Miocardio con Elevación del ST/fisiopatología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios ProspectivosRESUMEN
BACKGROUND: High aortic stiffness has been shown to be a strong predictor of morbidity and mortality in the general population and several patient cohorts. However, in patients after ST-elevation myocardial infarction, the prognostic value of high aortic stiffness is unknown so far. METHODS AND RESULTS: This prospective observational study included 160 consecutive patients with first acute ST-elevation myocardial infarction. Aortic pulse wave velocity (PWV) was measured 2 (interquartile range 2-4 days) days after infarction using cardiac magnetic resonance imaging. The primary end point was defined as a composite end point of major adverse cardiac and cerebrovascular events (MACCE) comprising death, nonfatal myocardial reinfarction, new congestive heart failure, and stroke. During a median follow-up of 1.2 years (interquartile range 1.0-3.1 years), 19 (12%) MACCE events occurred. Kaplan-Meier analysis showed a significantly lower MACCE-free survival in patients with high PWV (PWV >7.3 m/s, log-rank P=0.003). Multivariable Cox regression analysis revealed PWV >7.3 m/s to be an independent predictor of MACCE after adjustment for age, sex, mean blood pressure, N-terminal pro-brain natriuretic peptide levels, presence of multivessel disease, and left ventricular stroke volume (hazard ratios ≥3.5; 95% confidence interval 1.4-13.3; all P≤0.018). In reclassification analysis the addition of PWV to a risk model comprising major clinical prognostic parameters led to a net reclassification improvement of 0.11 (95% confidence interval 0.06-0.17; P<0.001). CONCLUSIONS: Increased aortic stiffness is an independent predictor of MACCE after acute ST-elevation myocardial infarction. Moreover, the assessment of aortic stiffness in addition to classical risk factors significantly improved early risk stratification.