RESUMEN
ABSTRACT: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been shown to reduce the risk of cardiovascular mortality and hospitalizations in patients with heart failure (HF) with preserved or reduced ejection fraction (HFpEF or HFrEF). The mechanism for this benefit is not clear. Endothelial progenitor cells (EPCs) are bone marrow-derived cells able to differentiate into functional endothelial cells and participate in endothelial repair. The aim of this study was to evaluate the effect of SGLT-2 inhibitors on the level and function of EPCs in patients with HF. We enrolled 20 patients with symptomatic HF, 12 with HFrEF and 8 with HFpEF (aged 73.3 ± 10.2 years, 95% men). Blood samples were drawn at 2 time points: baseline and ≥3 months after initiation of SGLT-2 inhibitor therapy. Circulating EPC levels were evaluated by expression of vascular endothelial growth factor receptor-2 (VEGFR-2), CD34, and CD133 by flow cytometry. EPC colony forming units (CFUs) were quantified after 7 days in culture. The proportion of cells that coexpressed VEGFR-2 and CD34 or VEGFR-2 and CD133 was higher following 3 months of SGLT-2 inhibitors [0.26% (interquartile range, IQR 0.10-0.33) versus 0.55% (IQR 0.28-0.91), P = 0.002; 0.12% (IQR 0.07-0.15) versus 0.24% (IQR 0.15-0.39), P = 0.001, respectively]. EPC CFUs were also increased following SGLT-2 inhibitor treatment [23 (IQR 3.7-37.8) versus 79.4 (IQR 25.1-110.25) colonies/10 6 cells, P = 0.0039]. In patients with symptomatic HF, both HFpEF and HFrEF, treatment with SGLT-2 inhibitors is associated with an increase in the level and function of circulating EPCs. This augmentation in EPCs may be a contributing mechanism to the clinical benefit of SGLT-2 inhibitors in patients with HF.
Asunto(s)
Células Progenitoras Endoteliales , Insuficiencia Cardíaca , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Volumen Sistólico , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Masculino , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Células Progenitoras Endoteliales/efectos de los fármacos , Células Progenitoras Endoteliales/metabolismo , Células Progenitoras Endoteliales/patología , Anciano , Femenino , Persona de Mediana Edad , Resultado del Tratamiento , Anciano de 80 o más Años , Células Cultivadas , Volumen Sistólico/efectos de los fármacos , Factores de Tiempo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Biomarcadores/sangre , Antígenos CD34/metabolismo , Antígenos CD34/sangre , Antígeno AC133/metabolismo , Función Ventricular Izquierda/efectos de los fármacos , Transportador 2 de Sodio-Glucosa/metabolismoRESUMEN
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a common clinical entity, with a mechanism that appears to involve endothelial dysfunction of the cardiac microcirculation. Endothelial progenitor cells (EPC) are bone marrow derived cells that are able to differentiate into functional endothelial cells and participate in endothelial surface repair. OBJECTIVES: To compare the level and function of EPCs in patients with HFpEF compared with heart failure with reduced ejection fraction (HFrEF) and control subjects. METHODS: We enrolled 21 patients with HFpEF (LVEF ≥ 50%, age 74.5 ± 9.9 years, 43% men, 48% diabetes), 20 patients with HFrEF (LVEF < 40%, age 70 ± 11.5 years, 90% men, 60% diabetes), and 11 control subjects with cardiovascular risk factors (age 53.3 ± 6.1years, 90% men, 64% diabetes). Circulating EPC levels were evaluated by expression of vascular endothelial growth factor receptor-2 (VEGFR-2), CD34, and CD133 by flow-cytometry. EPCs colony forming units (CFUs) were quantified after 7 days in culture. RESULTS: The proportion of cells that co-expressed VEGFR-2 and CD34 or VEGFR-2 and CD133 was similar among the HFpEF and HFrEF groups, and significantly lower than in the control group. The number of EPC-CFUs was also similar among the two heart failure groups and significantly lower than the control group. CONCLUSIONS: Patients with HFpEF, like HFrEF, have significant reduction in EPC level and function.
Asunto(s)
Antígeno AC133/sangre , Células Progenitoras Endoteliales/metabolismo , Endotelio Vascular , Insuficiencia Cardíaca , Volumen Sistólico , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangre , Anciano , Ensayo de Unidades Formadoras de Colonias/métodos , Circulación Coronaria , Correlación de Datos , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Femenino , Factores de Riesgo de Enfermedad Cardiaca , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Microcirculación , Persona de Mediana EdadRESUMEN
Dominant missense mutations in the amyloid ß (Aß) precursor protein (APP) gene have been implicated in early onset Alzheimer disease. These mutations alter protein structure to favor the pathologic production of Aß. We report that homozygous nonsense mutations in APP are associated with decreased somatic growth, microcephaly, hypotonia, developmental delay, thinning of the corpus callosum, and seizures. We compare the phenotype of this case to those reported in mouse models and demonstrate multiple similarities, strengthening the role of amyloid precursor protein in normal brain function and development. Ann Neurol 2016;80:456-460.
Asunto(s)
Precursor de Proteína beta-Amiloide/genética , Cuerpo Calloso/patología , Discapacidades del Desarrollo/genética , Microcefalia/genética , Hipotonía Muscular/genética , Convulsiones/genética , Consanguinidad , Humanos , Lactante , Masculino , Mutación , FenotipoRESUMEN
It is characterized by chemical and sometimes clinical hyperthyroidism, without evidence of thyroid autoimmunity that resolves spontaneously by 16 weeks gestation without significant obstetrical complications.