RESUMEN
PURPOSE: To describe the evolution of the serum levels of soluble HLA-G (s-HLA-G) during the first 12 months after heart transplantation (HT) and to correlate it with clinical outcomes. METHODS: Observational study based in a single-center cohort of 59 patients who underwent HT between December-2003 and March-2010. Soluble HLA-G levels were measured from serum samples extracted before HT, and 1, 3, 6 and 12 months after HT. The cumulative burden of s-HLA-G expression during the first post-transplant year was assessed by means of the area under the curve (AUC) of s-HLA-G levels over time and correlated with the acute rejection burden -as assessed by a rejection score-, the presence of coronary allograft vasculopathy (CAV) grade ≥ 1 and infections during the first post-transplant year; as well as with long-term patient and graft survival. Mean follow-up was 12.4 years. RESULTS: Soluble HLA-G levels decreased over the first post-transplant year (p = 0.020). The AUC of s-HLA-G levels during the first post-transplant year was higher among patients with infections vs. those without infections (p = 0.006). No association was found between the AUC of s-HLA-G levels and the burden of acute rejection or the development of CAV. Overall long-term survival, long-term survival free of late graft failure and cancer-free survival were not significantly different in patients with an AUC of s-HLA-G levels higher or lower than the median of the study population. CONCLUSIONS: Soluble HLA-G levels decreased over the first year after HT. Higher HLA-G expression was associated with a higher frequency of infections, but not with the burden of acute rejection or the development of CAV, neither with long-term patient or graft survival.
Asunto(s)
Antígenos HLA-G , Evaluación del Resultado de la Atención al Paciente , Receptores de Trasplantes , Humanos , Rechazo de Injerto/metabolismo , Supervivencia de Injerto/fisiología , Trasplante de Corazón/efectos adversos , Antígenos HLA-G/sangre , Antígenos HLA-G/químicaRESUMEN
BACKGROUND: Acute cellular rejection (ACR) is a major complication in heart transplantation (HTx). Endomyocardial biopsy is the reference method for early detection of ACR, but a new non-invasive approach is needed. Tentative candidates could be circulating microRNAs. This study aimed to discover and validate microRNAs in serum for ACR detection after HTx. METHODS: This prospective, observational, single-center study included 121 HTx patients. ACR was graded according to International Society of Heart and Lung Transplantation classification (0R-3R). First, in the discovery phase, microRNA expression profile was carried out in serum samples from patients at pre-rejection, during, and post-rejection time (0RS1â¯ââ¯2RS2`â¯ââ¯0RS3). Relative expression (2-∆Cq) of 179 microRNAs per sample was analyzed by reverse transcription quantitative polymerase chain reaction. Second, a microRNA with a significant rise and fall pattern during ACR was selected for the next validation phase, where it was analyzed (reverse transcription quantitative polymerase chain reaction) in serum samples from 2 groups of patients: the no-ACR group (0R grade) and the ACR group (≥2R grade). Finally, a sensitivity analysis (receiver operating characteristic curve) was done to assess microRNA accuracy for ACR detection in HTx. RESULTS: A total of 21 ACR episodes (0RS1â¯ââ¯2RS2â¯ââ¯0RS3) with their respective serum samples (nâ¯=â¯63) were included in the discovery phase. Among the 179 microRNAs analyzed, only miR-181a-5p met the rise and fall criteria. In the validation phase, miR-181a-5p relative expression (2-∆Cq) in the ACR group (nâ¯=â¯45) was significantly overexpressed (p < 0.0001) vs the no-ACR group (nâ¯=â¯45). miR-181a-5p showed an area under the curve of 0.804 (95% confidence interval: 0.707-0.880); sensitivity and specificity of 78% and 76%, respectively; and a negative predicted value of 98%. CONCLUSIONS: miR-185a-5p in serum is a candidate as a non-invasive ACR biomarker (area under the curveâ¯=â¯0.80 and negative predicted valueâ¯=â¯98%). Thus, this biomarker could reduce the need for endomyocardial biopsies and the associated risks and costs of this invasive procedure.
Asunto(s)
Rechazo de Injerto/sangre , Trasplante de Corazón/efectos adversos , MicroARNs/sangre , Adulto , Biomarcadores/sangre , Femenino , Estudios de Seguimiento , Rechazo de Injerto/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Curva ROCRESUMEN
INTRODUCTION: One of the main problems involved in heart transplantation (HT) is antibody-mediated rejection (AMR). Many aspects of AMR are still unresolved, including its etiology, diagnosis and treatment. In this project, we hypothesize that variants in genes involved in B-cell biology in HT patients can yield diagnostic and prognostic information about AMR. METHODS: Genetic variants in 61 genes related to B-cell biology were analyzed by next generation sequencing in 46 HT patients, 23 with and 23 without AMR. RESULTS: We identified 3 single nucleotide polymorphisms in ITGA4 gene (c.1845G>A, c.2633A>G, and c.2883C>T) that conformed the haplotype AGT-ITGA4. This haplotype is associated with the development of AMR. Moreover, AMR patients with the haplotype AGT-ITGA4 present lower levels of integrin α-4 in serum samples compared to the reference GAC haplotype in control patients. CONCLUSION: We can conclude that polymorphisms in genes related to the biology of B-cells could have an important role in the development of AMR. In fact, the AGT haplotype in ITGA4 gene could potentially increase the risk of AMR.
Asunto(s)
Anticuerpos/efectos adversos , Rechazo de Injerto/genética , Haplotipos/genética , Trasplante de Corazón , Integrinas/genética , Simulación por Computador , Femenino , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
INTRODUCTION AND OBJECTIVES: Circulating galectin-3 (Gal-3) is elevated and significantly correlates with all-cause and cardiovascular mortality in patients with heart failure. However, the relationship between serum Gal-3 and heart transplant (HT) outcomes is unclear. The aim of this study was to describe the longitudinal trend and prognostic value of Gal-3 levels after HT. METHODS: Banked serum samples were available from 122 HT recipients, collected before transplant and at 1, 3, 6, and 12 months posttransplant. Gal-3 levels in these serum samples were measured by enzyme immune assay. Multivariable Cox regression was performed to determine the prognostic value of 12-month posttransplant Gal-3 serum levels. The primary endpoint was the composite variable all-cause death or graft failure over long-term posttransplant follow-up. RESULTS: Circulating Gal-3 concentration steadily decreased during the first year after HT (median values: pretransplant, 19.1 ng/mL; 1-year posttransplant, 14.6 ng/mL; P<.001). Circulating Gal-3 levels 1-year posttransplant were associated with an increased risk of all-cause death or graft failure (adjusted HR per 1 ng/mL, 1.04; 95%CI, 1.01-1.08; P=.008). The predictive accuracy of this biomarker was moderate: area under the ROC curve, 0.72 (95%CI, 0.60-0.82; P<.001). CONCLUSIONS: Circulating Gal-3 steadily decreased during the first year after HT. However, 1-year posttransplant Gal-3 serum levels that remained elevated were associated with increased long-term risk of death and graft failure.
Asunto(s)
Galectina 3/sangre , Rechazo de Injerto/sangre , Trasplante de Corazón , Biomarcadores/sangre , Causas de Muerte/tendencias , Femenino , Estudios de Seguimiento , Rechazo de Injerto/epidemiología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Pronóstico , Curva ROC , Estudios Retrospectivos , Factores de Riesgo , España/epidemiología , Factores de TiempoRESUMEN
BACKGROUND: Heart transplantation (HT) is a life-saving treatment for patients with end-stage heart failure. One of the main problems after HT is the humoral response termed antibody-mediated rejection (AMR). Complement activation plays a key role in AMR contributing to graft damage. The aim of this study was to analyze genetic variants in genes related to the complement pathways that could be associated with the development of AMR. METHODS: Analysis of 51 genes related to the complement pathway was performed by next-generation sequencing in 46 HT recipients, 23 with and 23 without AMR. Statistical analysis was performed with SNPstats and R. RESULTS: We identified 2 single nucleotide polymorphisms, 1 in the mannose-binding lectin 2 gene (p.Gly54Asp-MBL2) and 1 in the complement factor properdin gene (p.Asn428(p=)-CFP), that showed significant association with the absence and development of AMR, respectively. Moreover, the presence of the rare allele in p.Gly54Asp-MBL2 control patients correlated with an immunodeficiency of mannose-binding lectin (6.24 ng/ml vs 207.50 ng/ml, p < 0.01), whereas the presence of the rare allele p.Asn428(p=)-CFP in patients with AMR correlated with higher levels of properdin protein (14.65 µg/ml vs 10.77 µg/ml, p < 0.05). CONCLUSIONS: AMR is a complex phenotype affected by many recipient factors. Variants in p.Gly54Asp-MBL2 and p.Asn428(p=)-CFP genes, encoding mannose-binding lectin 2 and properdin, may influence the risk of AMR.
Asunto(s)
Activación de Complemento/genética , Rechazo de Injerto/genética , Trasplante de Corazón , Lectina de Unión a Manosa/genética , Polimorfismo de Nucleótido Simple/genética , Properdina/genética , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/cirugía , Humanos , Masculino , Persona de Mediana EdadAsunto(s)
Rechazo de Injerto/complicaciones , Trasplante de Corazón , Miocardio/metabolismo , Neoplasias/etiología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Anciano , Femenino , Rechazo de Injerto/metabolismo , Rechazo de Injerto/patología , Humanos , Masculino , Persona de Mediana Edad , Miocardio/patología , Neoplasias/metabolismo , Neoplasias/patología , Transducción de Señal , Receptores de TrasplantesRESUMEN
BACKGROUND: Ivabradine, a selective bradycardic drug, inhibits the If. In patients with heart failure (HF), ivabradine reduces the risk of rehospitalization and mortality. The average heart rate (HR) reduction is 8-10 beats, although clinical trials reveal interindividual variability. The aim of the study is to identify variants associated with HR reduction produced by ivabradine in genes involved in the drug metabolism (CYP3A4) or related to the drug target (HCN4). METHODS: In an exploratory cohort (n = 11), patients started on ivabradine were genotyped and the HR reduction was studied. RESULTS: The mean HR reduction after the treatment was 18.10 ± 12.26 bpm. The HR reduction was ≥ 15 bpm in 3 patients and > 5 and < 15 bpm in 7 patients. Four synonymous variants, L12L, L520L, P852P, and P1200P, were detected in the HCN4 gene (frequency = 0.045, 0.045, and 0.681, respectively). Moreover, the CYP3A4*1F and CYP3A4*1B were found in one patient each and CYP3A4*1G was presented in 3 patients. CONCLUSIONS: This is the first study using an exploratory pharmacogenetic approach that attempts to explain interindividual variability in ivabradine HR reduction. However, more research must be undertaken in order to determine the role of variants in HCN4 and CYP3A4 genes in response to ivabradine.