Circulating Dipeptidyl Peptidase 3 levels, an Antagonist of Angiotensin-(1–7), in Acute Heart Failure: Insights from the PUSH-AHF trial

BACKGROUND: Angiotensin-(1-7) promotes vasodilation and counteracts angiotensin II in the vasculature and kidneys, while dipeptidyl peptidase 3 (DPP3) inactivates Ang-(1-7). Although circulating DPP3 (cDPP3) has been studied in chronic heart failure (HF), data in acute HF are limited. We evaluated cDPP3 levels and their association with clinical characteristics, decongestive response, and outcomes in acute HF. METHOD: We analyzed patients enrolled in the randomized PUSH-AHF trial comparing natriuresis-guided diuretic therapy with standard of care (SOC) in acute HF. cDPP3 levels were measured at baseline, 24, 48 and 72 hours, and at discharge. Associations between cDPP3 levels, clinical characteristics, 24-hour natriuresis, and the combined endpoint of 180-day all-cause mortality or HF hospitalization were assessed. Additionally, we evaluated whether diuretic treatment strategy modified these associations. RESULTS: Baseline cDPP3 was available in 287/310 patients (93%; mean age 73±12, 43% female) with a median concentration of 39 (26-62) ng/mL. cDPP3 decreased significantly within 24 hours (-17%, p<0.01) and stabilized thereafter. Both the lowest and highest quartiles were associated with lower eGFR, higher urea, and higher NT-proBNP levels (all p<0.03). In higher cDPP3 quartiles, natriuresis-guided diuretic therapy resulted in greater 24-hour natriuresis and diuresis compared with SOC; however, no significant treatment-cDPP3 interaction was observed. cDPP3 levels did not modify the treatment effect on the overall neutral combined endpoint. CONCLUSION: Higher cDPP3 concentrations are associated with impaired kidney function and reduced diuretic response in acute HF. Natriuresis-guided therapy improved decongestion across cDPP3 strata. Further studies should clarify the clinical role of cDPP3 in acute HF.