Hyaluronan and Syndecan-1: Linking Glycocalyx Degradation to Development and Progression of Heart Failure With Preserved Ejection Fraction

Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by chronic low-grade inflammation, which influences endothelial function, affecting glycocalyx integrity, barrier permeability, and cell adhesion. The role of endothelial glycocalyx shedding in the onset and progression of HFpEF remains poorly understood. Our aim was to investigate the association of glycocalyx degradation biomarkers, hyaluronan and syndecan-1, with patient characteristics and clinical outcomes in HFpEF and at population level. Methods: Circulating hyaluronan and syndecan-1 concentrations were assessed in a population-based cohort (STANISLAS [Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux], n=959) and a cohort with HFpEF (NETDiamond [New Targets in Diastolic Heart Failure: From Comorbidities to Personalized Medicine], n=86). Results: Hyaluronan levels increased with age in both the population cohort and the cohort with HFpEF. Higher hyaluronan concentrations were associated in adjusted analyses with features of adverse cardiac remodeling (higher left atrial volume index and left ventricular mass index) in both cohorts and with higher peak early mitral inflow velocity/peak early diastolic mitral annular velocity in the cohort with HFpEF. Syndecan-1 was negatively associated with left ventricular mass index in the population cohort but not in the cohort with HFpEF where a positive association with features of adverse cardiac remodeling was found. In HFpEF, higher concentrations of both hyaluronan and syndecan-1 were significantly associated with increased rates of cardiovascular events. Conclusions: Hyaluronan increases with age and is consistently associated with adverse cardiac remodeling across the spectrum of cardiovascular risk. In HFpEF, a manifestation of advanced cardiovascular disease, both hyaluronan and syndecan-1 associate with a higher risk of events. These findings suggest that glycocalyx degradation markers provide clinically relevant information across different stages of disease. Whether such markers may serve as therapeutic targets should be further explored.