Heparan Sulfate and Its Associations with Biochemical and Echocardiographic Parameters in Patients with Chronic Heart Failure Stratified by Cystatin C-Based Estimated Glomerular Filtration Rate.
Keywords:
chronic heart failure, heparan sulfate, endothelial glycocalyx, estimated glomerular filtration rate, renal dysfunction, cardiorenal syndromeAbstract
Background: Endothelial glycocalyx degradation may contribute to vascular dysfunction, systemic inflammation, and renal impairment in chronic heart failure (CHF). Heparan sulfate, a major component of the endothelial glycocalyx, is released into the circulation following glycocalyx injury.
Objective: To evaluate circulating heparan sulfate concentrations in patients with clinically stable CHF stratified by cystatin C-based estimated glomerular filtration rate (eGFR) and to examine their associations with renal, inflammatory, neurohormonal, and echocardiographic parameters.
Methods: This cross-sectional observational study included 100 patients with New York Heart Association functional class II–III CHF and 32 age- and sex-matched controls. Patients with CHF were stratified into Group I (eGFR 60–89 mL/min/1.73 m²; n = 50) and Group II (eGFR ≥90 mL/min/1.73 m²; n = 50). Serum heparan sulfate, cystatin C, N-terminal pro-B-type natriuretic peptide (NT-proBNP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) concentrations were measured. Echocardiographic parameters were assessed using standard methods. Associations were evaluated using Spearman’s rank correlation analysis, and the discriminatory performance of heparan sulfate was assessed using receiver operating characteristic curve analysis.
Results: Serum heparan sulfate concentrations were significantly higher in Group I than in Group II (236.2 ± 5.5 vs. 176.7 ± 1.5 ng/mL; P < 0.001) and the control group (63.1 ± 2.8 ng/mL; P < 0.001). Compared with Group II, Group I had higher cystatin C concentrations (1.05 ± 0.02 vs. 0.76 ± 0.01 mg/L; P < 0.001), lower cystatin C-based eGFR (72.9 ± 1.3 vs. 101.8 ± 1.3 mL/min/1.73 m²; P < 0.001), higher NT-proBNP concentrations (1256.5 ± 14.64 vs. 1027.4 ± 15.44 pg/mL; P < 0.001), higher IL-6 concentrations (9.9 ± 0.3 vs. 8.3 ± 0.4 pg/mL; P < 0.01), and a higher E/e′ ratio (15.2 ± 0.25 vs. 10.5 ± 0.21; P < 0.001). In Group I, heparan sulfate correlated positively with cystatin C (rₛ = 0.68), IL-6 (rₛ = 0.53), TNF-α (rₛ = 0.49), NT-proBNP (rₛ = 0.62), and E/e′ (rₛ = 0.52), and inversely with eGFR (rₛ = −0.64) and left ventricular ejection fraction (rₛ = −0.48; all P < 0.001). Similar but weaker associations were observed in Group II. Receiver operating characteristic analysis yielded an area under the curve of 0.968 (95% confidence interval, 0.934–1.000; P < 0.001). A heparan sulfate cutoff of ≥191.0 ng/mL distinguished mildly reduced from preserved eGFR with 88.0% sensitivity and 94.0% specificity.
Conclusion: Circulating heparan sulfate concentrations were elevated in patients with clinically stable CHF and were highest among those with mildly reduced cystatin C-based eGFR. Higher heparan sulfate concentrations were associated with poorer renal filtration, greater systemic inflammatory and neurohormonal activity, lower left ventricular systolic function, and higher estimated left ventricular filling pressure. These findings support the potential value of heparan sulfate as an integrative research biomarker of endothelial glycocalyx injury within the cardiorenal continuum; however, its clinical utility requires validation in larger multicenter studies.
References
Rangaswami J, Bhalla V, Blair JEA, Chang TI, Costa S, Lentine KL, Lerma EV, Mezue K, Molitch M, Mullens W, Ronco C, Tang WHW, McCullough PA. Cardiorenal syndrome: classification, pathophysiology, diagnosis, and treatment strategies: a scientific statement from the American Heart Association. Circulation. 2019;139(16):e840-e878. doi:10.1161/CIR.0000000000000664.
McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599-3726. doi:10.1093/eurheartj/ehab368.
Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure. Circulation. 2022;145(18):e895-e1032. doi:10.1161/CIR.0000000000001063.
McDonagh TA, Metra M, Adamo M, et al. 2023 focused update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2023;44(37):3627-3639. doi:10.1093/eurheartj/ehad195.
Kidney Disease: Improving Global Outcomes CKD Work Group. KDIGO 2024 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2024;105(4S):S117-S314. doi:10.1016/j.kint.2023.10.018.
Tang WHW, Bakitas MA, Cheng XS, Fang JC, Fedson SE, Fiedler AG, Martens P, McCallum WI, Ogunniyi MO, Rangaswami J, Bansal N. Evaluation and management of kidney dysfunction in advanced heart failure: a scientific statement from the American Heart Association. Circulation. 2024;150(16):e280-e295. doi:10.1161/CIR.0000000000001273.
Milusev A, Rieben R, Sorvillo N. The endothelial glycocalyx: a possible therapeutic target in cardiovascular disorders. Front Cardiovasc Med. 2022;9:897087. doi:10.3389/fcvm.2022.897087.
Masola V, Greco N, Gambaro G, Franchi M, Onisto M. Heparanase as active player in endothelial glycocalyx remodeling. Matrix Biol Plus. 2022;13:100097. doi:10.1016/j.mbplus.2021.100097.
Kim YH, Kitai T, Morales R, Kiefer K, Chaikijurajai T, Tang WHW. Usefulness of serum biomarkers of endothelial glycocalyx damage in prognosis of decompensated patients with heart failure with reduced ejection fraction. Am J Cardiol. 2022;176:73-78. doi:10.1016/j.amjcard.2022.04.036.
Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2015;16(3):233-271. doi:10.1093/ehjci/jev014.
Nagueh SF, Smiseth OA, Appleton CP, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2016;29(4):277-314. doi:10.1016/j.echo.2016.01.011.
Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012;367(1):20-29. doi:10.1056/NEJMoa1114248.
Liew H, Roberts MA, Pope A, McMahon LP. Endothelial glycocalyx damage in kidney disease correlates with uraemic toxins and endothelial dysfunction. BMC Nephrol. 2021;22(1):21. doi:10.1186/s12882-020-02219-4.
Stougaard EB, Winther SA, Amadid H, Frimodt-Moller M, Persson F, Hansen TW, Rossing P. Endothelial glycocalyx and cardio-renal risk factors in type 1 diabetes. PLoS One. 2021;16(7):e0254859. doi:10.1371/journal.pone.0254859.
Drost CC, Rovas A, Osiaevi I, Schughart K, Lukasz A, Linke WA, Pavenstadt H, Kumpers P. Interleukin-6 drives endothelial glycocalyx damage in COVID-19 and bacterial sepsis. Angiogenesis. 2024;27(3):411-422. doi:10.1007/s10456-024-09916-w.
Lagrange J, Jahangiri M, Baudry G, Mercier N, Monzo L, Lamiral Z, Duarte K, ter Maaten JM, Zannad F, Voors AA, Girerd N. Association between endothelial alterations, cardiac function, and outcomes from health to heart failure: insight from the STANISLAS, MEDIA-DHF, and BIOSTAT-CHF cohorts. J Am Heart Assoc. 2025;14(11):e040179. doi:10.1161/JAHA.124.040179.
