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. 2025 Aug;4(8):101999.
doi: 10.1016/j.jacadv.2025.101999. Epub 2025 Jul 24.

Modification of the Association of B-Type Natriuretic Peptides With Mortality and Hospitalization Outcomes by Sex

David Bobrowski  1 , Husam Abdel-Qadir  2 , Candace D McNaughton  3 , Anna Chu  4 , Xuesong Wang  4 , Peter C Austin  5 , Barbara S Doumouras  6 , Karem Abdul-Samad  7 , Peter A Kavsak  8 , Michael E Farkouh  9 , James L Januzzi  10 , Heather J Ross  11 , Douglas S Lee  12
Affiliations

Modification of the Association of B-Type Natriuretic Peptides With Mortality and Hospitalization Outcomes by Sex

David Bobrowski et al. JACC Adv. 2025 Aug.

Abstract

Background: The effects of sex on the prognostic implications of natriuretic peptide (NP) elevation have not been fully elucidated in the population.

Objectives: The purpose of this study was to examine if sex modifies associations of NPs with mortality and hospitalization.

Methods: In a population-based retrospective cohort study, we identified all patients (aged ≥40 years) undergoing NP testing in Ontario, Canada (2015-2020). We examined for the presence of sex-by-NP interactions for 1-year outcomes and conducted sex-specific analyses for continuously increasing NP concentrations.

Results: We studied 91,017 individuals with B-type natriuretic peptide (BNP) tests (median 75 years; 48.0% females) and 81,578 individuals with N-terminal pro-BNP (NT-proBNP) tests (74 years; 48.6% females). Adjusted 1-year risks of all-cause mortality at any given NP concentration were higher in males than females. For example, 1-year mortality at a BNP of 400 ng/L was 16.8% in females and 21.6% in males. At an NT-proBNP of 900 ng/L, 1-year mortality was 14.2% in females and 18.5% in males. However, there were also significant sex interactions with BNP (P = 0.002) and NT-proBNP (P = 0.03) for mortality outcomes. When we examined cardiovascular hospitalizations, there was also a significant sex-by-NP interaction. For BNP, the risk of cardiovascular hospitalization was higher in males at lower concentrations but was higher in females at higher concentrations (P-interaction = 0.005). For NT-proBNP, the risk of cardiovascular hospitalization was higher in males at lower NP concentrations, but the gap narrowed at higher NP levels (P interaction = 0.03).

Conclusions: Sex modifies the association between NP concentrations and all-cause mortality or cardiovascular hospitalizations. Prognostically, interpretation of NP levels should consider effect modification by sex.

Keywords: B-type natriuretic peptide; heart failure; hospitalization; mortality; natriuretic peptides; sex.

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Conflict of interest statement

Funding support and author disclosures This study was supported by a Foundation grant from the Canadian Institutes of Health Research (grant # FDN 148446) and also supported by the ICES, which is funded by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long-Term Care (MLTC). Dr Abdel-Qadir was supported by a National New Investigator Award from the Heart and Stroke Foundation of Canada and is currently supported by Tier 2 Canada Research Chair in Cardiovascular Disease Epidemiology and Outcomes. Dr McNaughton is supported by the Sunnybrook Research Institute, the Practice Plan of the Department of Emergency Services at Sunnybrook Health Sciences Centre and the University of Toronto. Dr Lee is the Ted Rogers Chair in Heart Function Outcomes, University Health Network, University of Toronto. Dr Doumouras is supported by the Women in Cardiology Fund from the Temerty Faculty of Medicine, University of Toronto. Dr Kavsak has received grants/reagents/consultant/advisor/honoraria from diagnostic companies that manufacture NP assays and materials for testing, including Abbott Laboratories, Abbott Point of Care, Beckman Coulter, Ortho Clinical Diagnostics, Quidel, Randox Laboratories, Roche Diagnostics, Siemens Healthcare Diagnostics, and Thermo Fisher Scientific. Dr Januzzi reports equity holdings in Imbria Pharma, Jana Care, and Fibrosys, current/recent grant support from Abbott, Applied Therapeutics, AstraZeneca, BMS, Novartis Pharmaceuticals, consulting income from Abbott Diagnostics, Beckman-Coulter, Jana Care, Janssen, Novartis, Prevencio, Quidel, and Roche Diagnostics, and serves on clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, CVRx, Medtronic, Pfizer, and Roche Diagnostics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Risk of All-Cause Mortality by NP Concentration, Stratified by Sex (A) Adjusted 1-year risk of all-cause mortality by BNP concentration, stratified by sex. Probability of 1-year all-cause mortality was higher in males (blue line, top) than females (red line, bottom). 95% CIs are plotted but are too narrow to be visible on figure. The sex-by-BNP interaction for the hazard of all-cause death was statistically significant (P = 0.002). (B) Adjusted 1-year risk of all-cause mortality by NT-proBNP concentration, stratified by sex. Probability of 1-year all-cause mortality was higher in males (blue line, top) than females (red line, bottom). 95% CIs are plotted but are too narrow to be visible on figure. The sex-by-NT-proBNP interaction for the hazard of all-cause death was statistically significant (P = 0.025). BNP = B-type natriuretic peptide; NT-proBNP = N-terminal pro-B-type natriuretic peptide.
Figure 2
Figure 2
Risk of CV Death by NP Concentration, Stratified by Sex (A) Adjusted 1-year risk of cardiovascular death by BNP concentration, stratified by sex. The adjusted cumulative incidence of cardiovascular death was comparable in males (blue line) and females (red line), with no sex-by-BNP interaction for cardiovascular death (P = 0.53). 95% CIs are plotted but are too narrow to be visible on figure. (B) Adjusted 1-year risk of cardiovascular death by NT-proBNP concentration, stratified by sex. The adjusted cumulative incidence of cardiovascular death was comparable in males (blue line) and females (red line), with no sex-by-NT-proBNP interaction for cardiovascular death (P = 0.97). 95% CIs are plotted, but are too narrow to be visible on figure. CV = cardiovascular; other abbreviations as in Figure 1.
Figure 3
Figure 3
Risk of CV Hospitalization by NP Concentration, Stratified by Sex (A) Adjusted 1-year risk of cardiovascular hospitalization by BNP concentration, stratified by sex. The adjusted cumulative incidence of cardiovascular hospitalization for males (blue line) and females (red line) exhibited a significant sex-by-BNP interaction (P < 0.001). 95% CIs are plotted, but are too narrow to be visible on figure. At high BNP levels, risk of cardiovascular hospitalization was higher in females than males. (B) Adjusted 1-year risk of cardiovascular hospitalization by NT-proBNP concentration, stratified by sex. The adjusted cumulative incidence of cardiovascular hospitalization for males (blue line) and females (red line) exhibited a trend toward a sex-by-BNP interaction (P = 0.062). 95% CIs are plotted, but are too narrow to be visible on figure. Risk of cardiovascular hospitalization was higher in males than females. Abbreviations as in Figures 1 and 2.
Figure 4
Figure 4
Risk of Heart Failure Hospitalization by NP Concentration, Stratified by Sex (A) Adjusted 1-year risk of heart failure hospitalization by BNP concentration, stratified by sex. Sex-by-BNP interaction for heart failure hospitalization was not significant (P = 0.68). 95% CIs are plotted, but are too narrow to be visible on figure. (B) Adjusted 1-year risk of heart failure hospitalization by NT-proBNP concentration, stratified by sex. Sex-by-NT-proBNP interaction for heart failure hospitalization was not significant (P = 0.20). 95% CIs are plotted, but are too narrow to be visible on figure. HF = heart failure; other abbreviations as in Figure 1.
Central Illustration
Central Illustration
Sex-Based Differences in the Prognostic Value of B-Type Natriuretic Peptides Adjusted 1-year risk of all-cause mortality by B-type natriuretic peptide (BNP, left) and N-terminal pro-BNP (NT-proBNP, right) concentrations demonstrates a sex-based difference, with higher mortality risk observed in males compared to females at any given peptide level. Significant interactions by sex were noted for both BNP (P = 0.002) and NT-proBNP (P = 0.03), indicating that sex modifies the association between natriuretic peptide levels and mortality. 95% CIs are plotted but are too narrow to be visible on figure. These findings demonstrate the importance of integrating sex-specific interpretation into heart failure risk prediction models that incorporate natriuretic peptide biomarkers.
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References

    1. Iwanaga Y., Nishi I., Furuichi S., et al. B-type natriuretic peptide strongly reflects diastolic wall stress in patients with chronic heart failure: comparison between systolic and diastolic heart failure. J Am Coll Cardiol. 2006;47(4):742–748. doi: 10.1016/j.jacc.2005.11.030. - DOI - PubMed
    1. Chow S.L., Maisel A.S., Anand I., et al. Role of biomarkers for the prevention, assessment, and management of heart failure: a scientific statement from the American Heart Association. Circulation. 2017;135(22):e1054–e1091. doi: 10.1161/CIR.0000000000000490. - DOI - PubMed
    1. Ezekowitz J.A., O'Meara E., McDonald M.A., et al. 2017 comprehensive update of the Canadian Cardiovascular Society guidelines for the management of heart failure. Can J Cardiol. 2017;33(11):1342–1433. doi: 10.1016/j.cjca.2017.08.022. - DOI - PubMed
    1. Heidenreich P.A., Bozkurt B., Aguilar D., et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on clinical practice guidelines. J Am Coll Cardiol. 2022;79(17):1757–1780. doi: 10.1016/j.jacc.2021.12.011. - DOI - PubMed
    1. Ponikowski P., Voors A.A., Anker S.D., et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891–975. doi: 10.1002/ejhf.592. - DOI - PubMed