Multiple Plasma Biomarkers for Risk Stratification in Patients With Heart Failure and Preserved Ejection Fraction

• Published in: Journal of the American College of Cardiology 2020-03, Vol.75 (11), p.1281-1295
• Main Authors: Chirinos, Julio A., Orlenko, Alena, Zhao, Lei, Basso, Michael D., Cvijic, Mary Ellen, Li, Zhuyin, Spires, Thomas E., Yarde, Melissa, Wang, Zhaoqing, Seiffert, Dietmar A., Prenner, Stuart, Zamani, Payman, Bhattacharya, Priyanka, Kumar, Anupam, Margulies, Kenneth B., Car, Bruce D., Gordon, David A., Moore, Jason H., Cappola, Thomas P.
• Format: Article
• Language: English
• Subjects: Aged; biomarkers; Biomarkers - blood; Female; fibrosis; Heart Failure - blood; Heart Failure - mortality; HFpEF; Humans; inflammation; kidney; liver; Machine Learning; Male; Middle Aged; Penn Heart Failure Study; Risk Assessment; TOPCAT trial; United States - epidemiology
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2019.12.069

Better risk stratification strategies are needed to enhance clinical care and trial design in heart failure with preserved ejection fraction (HFpEF). The purpose of this study was to assess the value of a targeted plasma multi-marker approach to enhance our phenotypic characterization and risk prediction in HFpEF. In this study, the authors measured 49 plasma biomarkers from TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial participants (n = 379) using a Multiplex assay. The relationship between biomarkers and the risk of all-cause death or heart failure-related hospital admission (DHFA) was assessed. A tree-based pipeline optimizer platform was used to generate a multimarker predictive model for DHFA. We validated the model in an independent cohort of HFpEF patients enrolled in the PHFS (Penn Heart Failure Study) (n = 156). Two large, tightly related dominant biomarker clusters were found, which included biomarkers of fibrosis/tissue remodeling, inflammation, renal injury/dysfunction, and liver fibrosis. Other clusters were composed of neurohormonal regulators of mineral metabolism, intermediary metabolism, and biomarkers of myocardial injury. Multiple biomarkers predicted incident DHFA, including 2 biomarkers related to mineral metabolism/calcification (fibroblast growth factor-23 and OPG [osteoprotegerin]), 3 inflammatory biomarkers (tumor necrosis factor-alpha, sTNFRI [soluble tumor necrosis factor-receptor I], and interleukin-6), YKL-40 (related to liver injury and inflammation), 2 biomarkers related to intermediary metabolism and adipocyte biology (fatty acid binding protein-4 and growth differentiation factor-15), angiopoietin-2 (related to angiogenesis), matrix metalloproteinase-7 (related to extracellular matrix turnover), ST-2, and N-terminal pro–B-type natriuretic peptide. A machine-learning–derived model using a combination of biomarkers was strongly predictive of the risk of DHFA (standardized hazard ratio: 2.85; 95% confidence interval: 2.03 to 4.02; p