Abstract
N-terminal-pro natriuretic peptide (NT-proBNP) levels are variably elevated in heart failure with preserved ejection fraction (HFpEF), even among patients with increased left ventricular filling pressures. NT-proBNP levels are prognostic in HFpEF, and NT-proBNP levels have been used as an inclusion criterion for several recent landmark randomized clinical trials but the underlying biologic differences between HFpEF patients with high and low NT-proBNP levels are not fully understood.
The primary objective of this study is to assess the correlates of NT-proBNP in the HFpEF population using a broad plasma proteomics approach (∼5000 plasma proteins along with knowledge-based pathway analysis).
We measured 4,928 proteins using an aptamer-based proteomic assay (SomaScan®) in available plasma samples from 2 cohorts: (1) TOPCAT trial participants in the Americas (n=218); (2) Participants with HFpEF enrolled in the Penn Heart Failure Study (PHFS, n=253). We assessed the relationship between plasma NT-proBNP and levels of other proteins using robust linear regression, with correction for multiple comparisons. We then performed pathway analysis to assess pathways associated with NT-proBNP.
NT-proBNP levels exhibited prominent proteome-wide associations in the TOPCAT and PHFS cohorts. Top proteins strongly associated with NT-proBNP in both cohorts included sushi, von Willebrand factor type A, EGF and pentraxin domain containing-1 (SVEP1; βTOPCAT=0.503; P<0.0001; βPHFS=0.51; P<0.0001), angiopoietin-2 (ANGPT2; βTOPCAT=0.573; P<0.0001; βPHFS=0.441; P<0.0001), and peroxidasin (PXDN; βTOPCAT=0.564; P<0.0001; βPHFS=0.497; P<0.0001). Canonical pathway analysis demonstrated consistent associations with multiple pathways related to fibrosis and inflammation. These included hepatic fibrosis, inhibition of matrix metalloproteases and the GP6 signaling pathway.
Circulating NT-proBNP levels exhibit prominent proteomic associations in HFpEF. Our findings suggest that higher NT-proBNP levels in HFpEF are a marker of fibrosis and inflammation. These findings will aid the interpretation of NT-proBNP levels in HFpEF and may guide the selection of participants in future HFpEF clinical trials.