Proteomic Correlates of the Urinary Protein/Creatinine Ratio in Heart Failure With Preserved Ejection Fraction.

Proteinuria is common in heart failure with preserved ejection fraction (HFpEF), but its biologic correlates are poorly understood. We assessed the relation between 49 plasma proteins and the urinary protein/creatinine ratio (UPCR) in 365 participants in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial. Linear regression and network analysis were used to represent relations between protein biomarkers and UPCR. Higher UPCR was associated with older age, a greater proportion of female gender, smaller prevalence of previous myocardial infarction, and greater prevalence of diabetes, insulin use, smoking, and statin use, in addition to a lower estimated glomerular filtration rate, hematocrit, and diastolic blood pressure. Growth differentiation factor 15 (GDF-15; β = 0.15, p <0.0001), followed by N-terminal proatrial natriuretic peptide (NT-proANP; β = 0.774, p <0.0001), adiponectin (β = 0.0005, p <0.0001), fibroblast growth factor 23 (FGF-23, β = 0.177; p <0.0001), and soluble tumor necrosis factor receptors I (β = 0.002, p <0.0001) and II (β = 0.093, p <0.0001) revealed the strongest associations with UPCR. Network analysis showed that UPCR is linked to various proteins primarily through FGF-23, which, along with GDF-15, indicated node characteristics with strong connectivity, whereas UPCR did not. In a model that included FGF-23 and UPCR, the former was predictive of the risk of death or heart-failure hospital admission (standardized hazard ratio 1.83, 95% confidence interval 1.49 to 2.26, p <0.0001) and/or all-cause death (standardized hazard ratio 1.59, 95% confidence interval 1.22 to 2.07, p = 0.0005), whereas UPCR was not prognostic. Proteinuria in HFpEF exhibits distinct proteomic correlates, primarily through its association with FGF-23, a well-known prognostic marker in HFpEF. However, in contrast to FGF-23, UPCR does not hold independent prognostic value.
Competing Interests: Declaration of Competing Interest Dr. Chirinos is supported by National Institutes of Health grants R01-HL 121510, U01-TR003734, 3U01TR003734-01W1, U01-HL160277, R33-HL-146390, R01-HL153646, K24-AG070459, R01-AG058969, R01-HL104106, P01-HL094307, R03-HL146874, R56-HL136730, R01 HL155599, R01 HL157264, R01HL155, and 1R01HL153646-01. He has recently consulted for Bayer, Sanifit, Fukuda-Denshi, Bristol-Myers Squibb, Johnson & Johnson, Edwards Life Sciences, Merck, NGM Biopharmaceuticals, and the Galway-Mayo Institute of Technology. He received University of Pennsylvania research grants from National Institutes of Health, Fukuda-Denshi, Bristol-Myers Squibb, Microsoft, and Abbott. He is named as inventor in a University of Pennsylvania patent for the use of inorganic nitrates/nitrites for the treatment of heart failure and on a patent application for the use of a novel biomarker (endotrophin) in heart failure with preserved ejection fraction. He has received payments for editorial roles from the American Heart Association, the American College of Cardiology, and Wiley. He has received research device loans from Atcor Medical, Fukuda-Denshi, Uscom, NDD Medical Technologies, Microsoft, and MicroVision Medical. The remaining authors have no competing interests to declare.
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