Endothelial Dysfunction in Hematological Patients: Sublingual Microscopy, Hyperspectral Imaging, and Serum Endothelial Markers
Authors: Simons Laura , Qadoura Muath , Buhl Jule , Sunderer Franziska , Korell Felix , Ikonomidis Ignatios , Dietrich Maximilian , Seidlitz Silvia , Vink Hans , Maier-Hein Lena , Schlenk Richard F. , Müller-Tidow Carsten , Dreger Peter , Luft Thomas 
Published: December 2024

Background: EASIX measured before conditioning therapy is a validated marker to predict risk of sepsis and mortality after allogeneic stem cell transplantation (alloSCT) in the context of acute GVHD, and in a variety of malignant and non-malignant conditions outside alloSCT. EASIX has now been reported as a novel marker of mortality of patients with coronary heart disease, with similar effects 2 months before as well as 6 months after cardiac intervention (1). However, the exact relationship of endothelial cell biology with EASIX requires further clarification. Endothelial cell responses to systemic or localized challenges are characterized by functional heterogeneity, therefore no ‘one fits all’ endothelial biomarker has been identified so far. Pre-transplantation markers predict risk of endothelial complications after alloSCT, still, outcome predictions for individual patients remain imprecise. We hypothesize, that the morphological substrate of EASIX is a reduced endothelial glycocalyx thickness resulting in direct interactions of leukocytes and platelets with receptors expressed on endothelial cells, thereby leading to cellular activation (increased LDH), loss of platelets due to activation and microembolism, as well as ensuing kidney damage. The prospective observational EndoCDO-H study (NCT05502887) was designed to compare local and systemic ways of assessing pre-transplant human endothelial function, including sublingual microscopy (Glycocheck®) for assessment of glycocalyx thickness and vessel density, hyperspectral imaging of digits and palms (Tivita®) for assessment of perfusion and tissue water (endothelial leakage), endothelial activation and stress index (EASIX-pre), and serum endothelial markers, in relation to outcome.

Methods: We performed sublingual microscopy in 169 patients within 7 days before start of conditioning therapy, and in 102 healthy volunteers. We calculated perfused boundary regions (PBR), vascular density and red blood cell velocity for vessel diameters between 4µm and 25µm. EASIX and serum markers were measured simultaneously. Hyperspectral imaging of digits and palms was performed in parallel in 72 of the patients and 28 healthy volunteers.

Results: Sublingual vascular density correlated with vascular perfusion of fingers and palms, PBR (sublingual glycocalyx thickness) with digital tissue water index, and EASIX correlated with PBR, tissue water index and indirectly with digital perfusion. EASIX-pre, PBR and NIR associated with early endothelial complications (sepsis, SOS/VOD/early bilirubinaemia) until d50 after alloSCT. Our results support the validity of EASIX and local imaging techniques to assess endothelial homeostasis. The moderate intercorrelations highlight the heterogeneity of the endothelial compartment and underline the need for multifaceted approaches to a comprehensive understanding of human endothelial function.

Conclusion: This study emphasizes the endothelial nature of EASIX, as high EASIX values correlate with reduced sublingual glycocalyx thickness, and with high tissue water index and reduced perfusion of digits and palms. Our results support the hypothesis that all of these methods reflect distinct aspects of the systemic integrity of the endothelium and the endothelial glycocalyx. Although a large variety of different conditions influence the individual EASIX parameters, one morphological substrate for high EASIX values appears to be a damaged glycocalyx. The correlation of differential endothelial measurements with prediction of clinical outcomes following alloSCT supports ongoing efforts to develop protective endothelial treatment strategies. Finally, risk stratification according to endothelial markers and degree of glycocalyx damage may help to improve patient outcomes.

(1) Finke, D. et al., EASIX (Endothelial Activation and Stress Index) predicts mortality in patients with coronary artery disease, in revision 2024