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. 2024 Feb;17(2):e011146.
doi: 10.1161/CIRCHEARTFAILURE.123.011146. Epub 2024 Feb 1.

Proteomic Associations of NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) in Heart Failure With Preserved Ejection Fraction

Joe David Azzo #  1 , Marie-Joe Dib #  2 , Loukas Zagkos  3 , Lei Zhao  4 , Zhaoqing Wang  4 , Ching-Pin Chang  4 , Christina Ebert  4 , Oday Salman  1 , Sushrima Gan  2 , Payman Zamani  1   2 , Jordana B Cohen  4   5 , Vanessa van Empel  6 , A Mark Richards  7   8 , Ali Javaheri  9   10 , Douglas L Mann  9 , Ernst R Rietzschel  11 , Peter H Schafer  4 , Dietmar A Seiffert  4 , Dipender Gill  3 , Stephen Burgess  12 , Francisco Ramirez-Valle  4 , David A Gordon  4 , Thomas P Cappola  1   2 , Julio A Chirinos  1   2
Affiliations

Proteomic Associations of NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) in Heart Failure With Preserved Ejection Fraction

Joe David Azzo et al. Circ Heart Fail. 2024 Feb.

Abstract

Background: NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels are variably elevated in heart failure with preserved ejection fraction (HFpEF), even in the presence of increased left ventricular filling pressures. NT-proBNP levels are prognostic in HFpEF and have been used as an inclusion criterion for several recent randomized clinical trials. However, the underlying biologic differences between HFpEF participants with high and low NT-proBNP levels remain to be fully understood.

Methods: We measured 4928 proteins using an aptamer-based proteomic assay (SOMAScan) in available plasma samples from 2 cohorts: (1) Participants with HFpEF enrolled in the PHFS (Penn Heart Failure Study; n=253); (2) TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) participants in the Americas (n=218). We assessed the relationship between SOMAScan-derived plasma NT-proBNP and levels of other proteins available in the SOMAScan assay version 4 using robust linear regression, with correction for multiple comparisons, followed by pathway analysis.

Results: NT-proBNP levels exhibited prominent proteome-wide associations in PHFS and TOPCAT cohorts. Proteins most strongly associated with NT-proBNP in both cohorts included SVEP1 (sushi, von Willebrand factor type-A, epidermal growth factor, and pentraxin domain containing 1; βTOPCAT=0.539; P<0.0001; βPHFS=0.516; P<0.0001) and ANGPT2 (angiopoietin 2; βTOPCAT=0.571; P<0.0001; βPHFS=0.459; P<0.0001). Canonical pathway analysis demonstrated consistent associations with multiple pathways related to fibrosis and inflammation. These included hepatic fibrosis and inhibition of matrix metalloproteases. Analyses using cut points corresponding to estimated quantitative concentrations of 360 pg/mL (and 480 pg/mL in atrial fibrillation) revealed similar proteomic associations.

Conclusions: 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.

Keywords: biomarkers; fibrosis; heart failure; inflammation; proteomics.

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Conflict of interest statement

Disclosures Dr Chirinos has recently consulted for Bayer, Sanifit, Fukuda-Denshi, Bristol Myers Squibb, Johnson & Johnson, Edwards Life Sciences, Merck, and the Galway-Mayo Institute of Technology. He received University of Pennsylvania research grants from the National Institutes of Health, Fukuda-Denshi, Bristol Myers Squibb, and Microsoft. He is named as an inventor in a University of Pennsylvania patent for the use of inorganic nitrates/nitrites in Heart Failure With Preserved Ejection Fraction. He has received research device loans from Atcor Medical, Fukuda-Denshi, Uscom, NDD Medical Technologies, Microsoft, and MicroVision Medical. Dr Zamani receives research support from Amgen. He has consulted for Pfizer and Vyaire. Dr Rietzschel has received unrestricted educational grants from Amgen, Merck Sharp & Dohme, AstraZeneca, Sanofi, and Unilever and speakers’ or consultancy fees from Daiichi Sankyo, Novo Nordisk, Boehringer Ingelheim, Servier, Amgen, Sanofi, Novartis, and Teva, all paid directly to Ghent University. He is named as inventor on patent applications for the use of plasma and urine protein biomarkers in heart failure. Dr Richards is supported by grants from Singapore National Medical Research Council and the Health Research Council of New Zealand. He holds the New Zealand Heart Foundation Chair in Cardiovascular Studies. In kind support and research grants are received from Roche Diagnostics, Abbott Laboratories, and Novo Nordisk. He is named on ≈30 cardiovascular biomarker patents. Dr Gill acknowledges support by the British Heart Foundation Centre of Research Excellence at Imperial College London (RE/18/4/34215). The other authors report no conflicts.

Figures

Figure 1
Figure 1. Proteome-wide association study of 4,996 plasma proteins on NT-proBNP levels.
Robust linear regressions were performed on the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT) and the Penn Heart Failure Study (PHFS) cohorts to identify proteins significantly associated with NT-proBNP.
Figure 2
Figure 2. Volcano plot demonstrating significant associations between all plasma proteins with plasma levels of N-terminal-pro BNP (NT-proBNP) after adjusting for covariates measured in (A) the Penn Heart Failure Study (PHFS, n=253) and (B) the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT, n=218).
The plots show standardized beta estimates against the log-10 p value. The nominal and alpha-corrected significance levels are represented by solid lines on the y-axis.
Figure 2
Figure 2. Volcano plot demonstrating significant associations between all plasma proteins with plasma levels of N-terminal-pro BNP (NT-proBNP) after adjusting for covariates measured in (A) the Penn Heart Failure Study (PHFS, n=253) and (B) the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT, n=218).
The plots show standardized beta estimates against the log-10 p value. The nominal and alpha-corrected significance levels are represented by solid lines on the y-axis.
Figure 3
Figure 3. Canonical pathway analysis of proteins observed to be significantly associated with plasma levels of NT-proBNP levels in (A) the Penn Heart Failure Study (PHFS, n=253) and (B) the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT, n=218).
PCA corrected p-value of 0.05 threshold was used to determine significance. Numbers at the end of the bars indicate the Z-score corresponding to direction and strength of association.
Figure 3
Figure 3. Canonical pathway analysis of proteins observed to be significantly associated with plasma levels of NT-proBNP levels in (A) the Penn Heart Failure Study (PHFS, n=253) and (B) the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT, n=218).
PCA corrected p-value of 0.05 threshold was used to determine significance. Numbers at the end of the bars indicate the Z-score corresponding to direction and strength of association.
Figure 4
Figure 4. Concordance between standardized beta estimates for proteome-wide association analyses in PHFS and TOPCAT.
See this image and copyright information in PMC

Comment in

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