Biomarker profile in stable Fontan patients

• Authors: Anita Saraf, Emory University; Christine De Staercke, Centers for Disease Control and Prevention; Ian Everitt, Emory University; Alice Haouzi, Emory University; Yi-An Ko, Emory University; Staci Jennings, Emory University; Jonathan Kim, Emory University; Fred Rodriguez III, Emory University; Andreas Kalogeropoulos, Emory University; Arshed Quyyumi, Emory University; Wendy Book, Emory University
• Journal Title: International Journal of Cardiology
• Volume: Volume 305
• Publisher: Elsevier Ireland Ltd. | 2020-04-15, Pages 56-62
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.ijcard.2020.01.012
• Subjects: Health Sciences, Oncology; Biology, Biostatistics; Biology, Bioinformatics; Health Sciences, Health Care Management
• Keywords: Science & Technology; Life Sciences & Biomedicine; Cardiac & Cardiovascular Systems; Cardiovascular System & Cardiology; Fontan; Biomarkers; Liver function; GDF-15; Tumor necrosis factor; Endothelial growth factor; Heart failure; Factor alpha; IV Collagen; Hepatocellular carcinoma; Kidney function; Elevated levels; Liver diseases; Cystatin C

Abstract

Background: As the population of adults with congenital heart disease (CHD) grows, cardiologists continue to encounter patients with complex anatomies that challenge the standard treatment of care. Single ventricle Fontan palliated patients are the most complex within CHD, with a high morbidity and mortality burden. Factors driving this early demise are largely unknown. Methods and Results: We analyzed biomarker expression in 44 stable Fontan outpatients (29.2 ± 10.7 years, 68.2% female) seen in the outpatient Emory Adult Congenital Heart Center and compared them to 32 age, gender and race matched controls. In comparison to controls, Fontan patients had elevated levels of multiple cytokines within the inflammatory pathway including Tumor Necrosis Factor-α (TNF-α) (p<0.001), Interleukin-6 (IL-6) (p<0.011), Growth Derived Factor-15 (GDF-15) (p<0.0001), β2-macroglobulin, (p=0.0006), stem cell mobilization: SDF-1α (p=0.006), extracellular matrix turnover: Collagen IV (p<0.0001), neurohormonal activation: Renin (p<0.0001), renal dysfunction: Cystatin C (p<0.0001) and Urokinase receptor (uPAR) (p=0.022), cardiac injury: Troponin-I (p<0.0004) and metabolism: Adiponectin (p=0.0037). Within our baseline -stable- Fontan patients, 50% had hospitalizations, arrhythmias and worsening hepatic function within 1 year. GDF-15 was significantly increased in Fontan patients with clinical events (p<0.0001). In addition, GDF-15 moderately correlated with longer duration of Fontan (r=0.55, p=0.01) and was elevated in atriopulmonary (AP) Fontan circulation. Finally, in a multivariate model, VEGF-D and Collagen IV levels were found to be associated with a change in MELDXI, a marker of liver function. Conclusion: Multiple clinical and molecular biomarkers are upregulated in Fontan patients, suggesting a state of chronic systemic dysregulation.