Abstract 12661: Prognostic Significance of Tubular Injury Biomarkers in Heart Failure With Preserved Ejection Fraction (HFpEF)

Abstract

Background: The onset and progression of CKD in HFpEF may be driven by different etiologies, including tubular injury, glomerular disease or interstitial remodeling. We assessed the prognostic significance of tubular injury assessed with a combination of plasma protein biomarkers. Methods: We analyzed data and samples from the TOPCAT trial. We utilized the SomaScan assay to measure tubular injury biomarkers: Alpha-1 microglobulin (A1M), Beta 2 microglobulin (B2M), neutrophil gelatinase associated lipocalin (NGAL), kidney injury molecule 1 (KIM1), and interleukin 18 (IL-18). Factor analysis was used to extract the common variability underlying these biomarkers. We assessed the relationship between factor scores and: (1) All-cause mortality; (2) The composite of death or heart failure hospital admission (DHFA). All hazard ratios (HR) are standardized (per unit increase in z score) to facilitate comparisons. Linear regression was used to assess the relationship of each factor to 4,746 other proteins, followed by pathway analyses. Results: There were 2 underlying factors: factor 1 was associated predominantly with KIM1, whereas factor 2 was strongly associated with NGAL. Both factors were associated with estimated GFR. Factor 1 was predominantly associated with diabetes, whereas factor 2 was predominantly associated with a lower mean arterial pressure. In a model that included the 2 factors, both were significantly and independently associated with DHFA (Factor 1 HR=1.75; 95%CI=[1.47,2.07]; P<0.0001; Factor 2 HR=1.37; 95%CI=[1.17,1.62]; P=0.0001), but only factor 1 was significantly associated with death (Factor 1 HR=1.22; 95%CI=[1.06,1.40]; P=0.0046; Factor 2 HR=1.23; 95%CI=[0.98,1.54]; P=0.066). In analyses that adjusted for estimated GFR and the MAGGIC risk score, Factor 1 was significantly associated with death and DHFA, whereas Factor 2 was only associated with DHFA. These factors were associated with pathways related to immunity, fibrosis, oxidative stress, cell death, and myocardial remodeling. Conclusion: Tubular injury is associated with adverse outcomes in HFpEF. This relationship is independent of baseline GFR, suggesting that ongoing injury contributes to poor outcomes and may represent a target for therapy.