Clinical Report: Levels of Circulating Dipeptidyl Peptidase 3 in Acute Heart Failure
Overview
This biomarker substudy of PUSH-AHF examines associations between circulating dipeptidyl peptidase 3 (cDPP3), clinical characteristics, decongestive response, and outcomes in acute heart failure (HF). It also evaluates whether cDPP3 concentrations modify the effects of natriuresis-guided diuretic therapy.
Background
Treatment options for acute HF remain limited, and congestion varies considerably among patients. Biomarkers reflecting underlying disease mechanisms may help characterize this variation.
DPP3 degrades bioactive peptides, including angiotensin II and angiotensin-(1–7). Preclinical studies link elevated circulating DPP3 to myocardial depression and impaired renal hemodynamics. Its role in acute HF, including its potential association with diuretic resistance, remains under investigation.
Data Highlights
Baseline cDPP3 measurements were available for 287 of 310 enrolled patients (93%).
Mean age was 73 years, and 43% were women.
Median baseline cDPP3 was 39 ng/mL (interquartile range, 26–62 ng/mL).
cDPP3 concentrations decreased by 17% within 24 hours (P < .01) and subsequently stabilized.
In the combined intermediate cDPP3 quartiles, 24-hour natriuresis was 424 mmol with natriuresis-guided therapy vs 355 mmol with standard care.
In the highest cDPP3 quartile, 24-hour natriuresis was 398 mmol with natriuresis-guided therapy vs 275 mmol with standard care.
The treatment-by-cDPP3 interaction for 24-hour natriuresis was not significant (P = .287).
Key Findings
Both the lowest and highest baseline cDPP3 quartiles were associated with lower estimated glomerular filtration rate and higher urea and N-terminal pro–B-type natriuretic peptide concentrations.
Higher baseline cDPP3 was associated with lower 24-hour natriuresis under standard care. This association was not observed with natriuresis-guided therapy.
Natriuresis-guided therapy increased 24-hour natriuresis in the intermediate and highest cDPP3 groups, but the treatment-by-cDPP3 interaction was not significant.
Plasma cDPP3 was measured at baseline, 24, 48, and 72 hours, and discharge, with measurement availability varying across time points.
cDPP3 did not significantly modify treatment effects on the combined endpoint of all-cause death or HF hospitalization within 180 days.
Clinical Implications
cDPP3 may reflect disease severity and early response to decongestive therapy. However, these exploratory findings do not establish cDPP3 as a marker for selecting treatment or demonstrate that cDPP3-guided management improves clinical outcomes. Its incremental value beyond established biomarkers remains uncertain.
The single-center design, missing measurements, and limited power to detect treatment interactions constrain interpretation. Hemolysis affected 14% of baseline samples and could increase measured cDPP3, although analyses excluding these samples yielded consistent results. The observational biomarker analysis cannot establish causality.
Conclusion
Higher cDPP3 concentrations are associated with reduced early natriuresis under standard care, an association that appears mitigated by natriuresis-guided therapy. Further research is needed to validate these findings and establish their clinical applicability.
Related Resources & Content
Natriuresis-guided diuretic therapy in acute heart failure: a pragmatic randomized trial — Ter Maaten JM, Beldhuis IE, Van der Meer P, Krikken JA, Postmus D, Coster JE, et al — Nature Medicine — 2023.
Natriuresis-guided therapy in acute heart failure: rationale and design of the Pragmatic Urinary Sodium-based treatment algoritHm in Acute Heart Failure (PUSH-AHF) trial — Ter Maaten JM, Beldhuis IE, Van der Meer P, Krikken JA, Coster JE, Nieuwland W, et al — European Journal of Heart Failure — 2022.
Dipeptidyl peptidase 3, a marker of the antagonist pathway of the renin–angiotensin–aldosterone system in patients with heart failure — Boorsma EM, Ter Maaten JM, Damman K, Van Veldhuisen DJ, Dickstein K, Anker SD, et al — European Journal of Heart Failure — 2021.
Circulating dipeptidyl peptidase 3 modulates systemic and renal hemodynamics through cleavage of angiotensin peptides — Picod A, Placier S, Genest M, Callebert J, Julian N, Zalc M, et al — Hypertension — 2024.
Circulating dipeptidyl peptidase 3 is a myocardial depressant factor: dipeptidyl peptidase 3 inhibition rapidly and sustainably improves haemodynamics — Deniau B, Rehfeld L, Santos K, Dienelt A, Azibani F, Sadoune M, et al — European Journal of Heart Failure — 2020.
