High Fibrinogen Levels Promote Erythrocyte-Erythrocyte Adhesion: A Cardiovascular Risk Factor in Heart Failure and Arterial Hypertension Patients

Abstract

Erythrocyte aggregation is an indicator of cardiovascular risk, which is influenced by plasma fibrinogen concentration. Fibrinogen levels are elevated during cardiovascular diseases. Our main goals were to understand how fibrinogen-erythrocyte binding influences erythrocyte aggregation and how it constitutes a cardiovascular risk factor in essential arterial hypertension (EAH) and chronic heart failure (CHF). Fibrinogen-erythrocyte and erythrocyte-erythrocyte adhesion measurements were conducted by atomic force microscopy (AFM)-based force spectroscopy. Upon increasing fibrinogen concentration, there was an increase in the work and force necessary for cell-cell detachment, both for healthy donors and EAH patients. Nevertheless, higher values were obtained for the EAH patients at each fibrinogen concentration. Fibrinogen-erythrocyte (un)binding forces were higher in EAH and CHF patients, when compared with the control group, despite a lower binding frequency. Ischemic CHF patients showed increased binding forces compared to non-ischemic patients. Differences between CHF patients and healthy donors, in terms of erythrocyte elasticity (Young's modulus) and AFM tip penetration depth into the cells were also assessed. Erythrocytes from non-ischemic patients presented higher stiffness than those from the other two groups. Nevertheless, a significantly higher cell penetration depth at the same applied force was observed for ischemic heart failure patients. Erythrocyte deformability (assessed as elongation index) results show that heart failure patients presented higher erythrocyte deformability than the control group at lower shear stresses, and lower deformability at higher shear stresses. This indicates that patients’ erythrocytes are more deformable than those from healthy donors in blood vessels with larger internal diameters; however, in smaller-diameter vessels the opposite trend exists. Finally, a 12-month clinical follow-up shows that CHF patients with higher fibrinogen-erythrocyte binding forces, probed by AFM at the beginning of the assessment, had a significantly higher probability of being hospitalized due to cardiovascular complications on the subsequent year. Our results show that AFM can be a promising tool for clinical prognosis, pinpointing those patients with increased risk for cardiovascular diseases.Guedes et al. (2016) Nature Nanotechnology, 11:687-92.