Objective:

To examine associations between circulating dipeptidyl peptidase 3 (cDPP3), clinical characteristics, decongestive response, and outcomes in acute heart failure (HF), and whether cDPP3 modifies the effects of natriuresis-guided diuretic therapy.

Approach:

• Patient Population: This biomarker substudy included 287 of 310 adults enrolled in the single-center, randomized PUSH-AHF trial comparing natriuresis-guided diuretic therapy with standard care. Main exclusions included severe renal impairment requiring ultrafiltration or dialysis and dyspnea attributable to another diagnosis.
• Biomarker Assessment: Plasma cDPP3 was measured using a luminometric immunoassay at baseline, 24, 48, and 72 hours, and discharge, with availability varying across time points.
• Study Outcomes: Dual primary endpoints were 24-hour natriuresis and time to first all-cause death or HF hospitalization within 180 days.
• Statistical Analysis: Analyses included group comparisons, regression models, treatment interaction tests, and longitudinal mixed-effects models. Findings were exploratory, without adjustment for multiple testing.

Key Findings:

• Median baseline cDPP3 was 39 ng/mL (interquartile range, 26–62 ng/mL). Concentrations decreased by 17% within 24 hours and subsequently stabilized.
• Both the lowest and highest 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.
• cDPP3 did not significantly modify treatment effects on the 180-day combined endpoint.

Interpretation:

cDPP3 may reflect disease severity and early decongestive response. Its incremental clinical value beyond established biomarkers remains uncertain, and the findings do not establish cDPP3 as a treatment-selection marker.

Limitations:

• The single-center substudy and missing measurements limit generalizability and robustness.
• The observational biomarker analysis cannot establish causality and was not powered to detect treatment interactions.
• Hemolysis affected 14% of baseline samples and could elevate measured cDPP3, although sensitivity analyses excluding these samples yielded consistent results.

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 clinical applicability.