Circulating dipeptidyl peptidase 3 is a myocardial depressant factor: dipeptidyl peptidase 3 inhibition rapidly and sustainably improves haemodynamics

Abstract

Aims Acute heart failure is a high mortality disease and its pathophysiology is not completely understood. Dipeptidyl peptidase 3 (DPP3) is a cytosolic enzyme involved in angiotensin II and enkephalins cleavage. The aim of this study was to investigate the association of circulating DPP3 (cDPP3) levels and mortality in cardiogenic shock patients and to determine the effects of high cDPP3 on organ function in a heart failure (HF) model in mice. Methods and results cDPP3 was measured in 174 patients in cardiogenic shock and high cDPP3 levels were associated with an increased short‐term mortality risk (standardized hazard ratio: 1.4 (1.1–1.8)) and severe organ dysfunction. Additionally, a rapid decrease in cDPP3 in cardiogenic shock patients within 24 h of admission was associated with a favourable outcome. This study showed that injection of DPP3 induced myocardial depression (−10 ± 2% of shortening fraction) and impaired kidney haemodynamics (+0.30 ± 0.02 of renal resistive index) in healthy mice. cDPP3 inhibition by Procizumab, a specific antibody directed against cDPP3, promptly normalized cardiac function and kidney haemodynamics in an acute heart failure mouse model, with a marked reduction in oxidative stress and inflammatory signalling. Conclusion Our study demonstrated cDPP3 is a newly discovered myocardial depressant factor, the levels of which at admission are associated with mortality in severe HF patients. Furthermore, inhibition of cDPP3 by Procizumab improved haemodynamics in a mouse model of HF. Our results suggest that DPP3 could be a new biomarker and biotarget for severe HF.

Circulating dipeptidyl peptidase 3 and alteration in haemodynamics in cardiogenic shock: results from the OptimaCC trial

“…DPP3 is a cytosolic enzyme involved in the cleavage of cardiovascular mediators. The present study confirms the previous observation that CS patients with high cDPP3 have worse haemodynamics, renal function, and mortality rate . Though association between high cDPP3 and occurrence of refractory shock remains unknown, a recent publication from our group showed that intravenous administration of DPP3 immediately depressed cardiac contraction while DPP3 inhibition restored cardiac contraction in a heart failure mouse model .…”

“…We found that high cDPP3 in the two consecutive days following admission was associated with bad outcomes while a drop in cDPP3 from high to low values was associated with a more favourable outcome. DPP3 is mainly an intracellular protein with a short half‐life . Accordingly, it could be suggested that persistent elevation of cDPP3 in some CS patients may be related to high cell death (necrosis) compared with CS patients who normalized cDPP3 values.…”

“…Circulating dipeptidyl peptidase 3 (cDPP3) is a protease involved in the degradation of angiotensin II and enkephalins . Recently, it has been shown that high values of cDPP3 were found in critically ill patients suffering from septic shock and CS . We hypothesize that cDPP3 might be associated with alterations in haemodynamics and survival in CS patients.…”

February 2020 at a glance: acute heart failure and cardio‐oncology

“…Circulating dipeptidyl peptidase 3 (cDPP3), a protease involved in angiotensin II and enkephalin degradation, was measured in patients with cardiogenic shock . High baseline cDPP3 was associated with increased short‐term mortality and more severe organ dysfunction and its rapid decrease within 24 h predicted a favourable outcome .…”

Circulating plasma dipeptidyl dipeptidase 3 and the prognosis of cardiogenic shock

“…cDPP3 has been implicated in pathophysiologic processes such as inflammation, blood pressure regulation, and pain modulation . Concentrations of cDDP3 have been found to be elevated in septic and cardiogenic shock . In vitro testing shows that cDPP3 is involved in angiotensin II regulation.…”