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 the current 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 VEGFR-2, CD34 and CD133 by flow-cytometry. EPCs colony forming units (CFUs) were quantified after 7 days in culture. The proportion of cells that co-expressed VEGFR-2 and CD34 or VEGFR-2 and CD133 was higher following 3 months of SGLT-2 inhibitors [0.26% (IQR 0.10-0.33) vs. 0.55% (IQR 0.28-0.91), P=0.002; 0.12% (IQR 0.07-0.15) vs. 0.24% (IQR 0.15-0.39), P=0.001, respectively]. EPCs-CFU were also increased following SGLT-2 inhibitor treatment [23 (IQR 3.7-37.8) vs. 79.4 (IQR 25.1-110.25) colonies/106 cells, P=0.0039]. In patients with symptomatic HF, both HFpEF and HFrEF, treatment with SGLT-2 inhibitors is associated with an increase in circulating EPCs level and function. This augmentation in EPCs may be a contributing mechanism to the clinical benefit of SGLT-2 inhibitors in HF patients.
ABSTRACT
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.
Subject(s)
AC133 Antigen/blood , Endothelial Progenitor Cells/metabolism , Endothelium, Vascular , Heart Failure , Stroke Volume , Vascular Endothelial Growth Factor Receptor-2/blood , Aged , Colony-Forming Units Assay/methods , Coronary Circulation , Correlation of Data , Endothelium, Vascular/metabolism , Endothelium, Vascular/physiopathology , Female , Heart Disease Risk Factors , Heart Failure/blood , Heart Failure/physiopathology , Humans , Male , Microcirculation , Middle AgedABSTRACT
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.
Subject(s)
Amyloid beta-Protein Precursor/genetics , Corpus Callosum/pathology , Developmental Disabilities/genetics , Microcephaly/genetics , Muscle Hypotonia/genetics , Seizures/genetics , Consanguinity , Humans , Infant , Male , Mutation , PhenotypeABSTRACT
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.
