Background: Dipeptidyl peptidase 3 (DPP3) is a cytosolic enzyme released during cellular injury and involved in the degradation of cardiovascular and endorphin mediators. DPP3 levels were found to be elevated in patients with sepsis, acute heart failure and cardiogenic shock. In experimental models of sepsis and acute heart failure, inhibition of circulating DPP3 restored cardiac function. The monoclonal antibody procizumab is currently being investigated in clinical trials in patients with cardiogenic shock and elevated circulating cDPP3 (cDPP3) levels. The purpose of this study was to assess the prognostic value of cDPP3 for cardiovascular outcomes in patients with acute myocardial infarction (AMI).
Methods: cDPP3 plasma concentrations were measured on admission in 6,540 patients with AMI enrolled in a German (n = 2,372) and a Swiss (n = 4,168) cohort. The primary endpoint was major adverse cardiovascular events (MACE: non-fatal myocardial infarction, non-fatal stroke or cardiovascular death) within 12 months. A secondary endpoint was all-cause death. The prognostic value of cDPP3 levels was assessed using Kaplan-Meier, multivariable Cox proportional hazards and variable importance analyses.
Results: The median age was 68 years in the German cohort and 63 years in the Swiss cohort, with 70% and 79% of participants being male, respectively. In the 12-month observation period, 127 and 261 subjects experienced MACE and all-cause death occurred in 134 and 146 individuals. Kaplan–Meier analyses revealed a stepwise increase of MACE and all-cause death across cDPP3 tertiles. Higher cDPP3 levels were consistently associated with increased risk of MACE and all-cause death in both cohorts when comparing the highest versus lowest cDPP3 tertile (German cohort: Hazard ratio (HR): 2.33; 95% confidence interval (CI): 1.46, 3.74; p=0.002; Swiss cohort: HR: 1.42; 95% CI: 1.05, 1.91; p=0.023). These results remained significant after multivariable adjustment for age, sex, hypertension, dyslipidemia, family history of cardiovascular disease, diabetes mellitus, creatinine, high-sensitivity C-reactive protein (hsCRP) and high-sensitivity-troponin T (hsTnT). Similar results have been observed for all-cause death. Patients in the highest versus lowest DPP3 tertile had approximately two-fold higher mortality risk in both populations. Variable importance analyses identified cDPP3 among the strongest independent predictors of outcome, ranking among established risk markers such as hsTnT and hsCRP for prediction of MACE and all-cause death. Associations were consistent across clinically relevant subgroups stratified after age, sex, hypertension, dyslipidemia, family history of cardiovascular disease and diabetes mellitus.
Conclusions: Across two large European AMI cohorts, elevated cDPP3 independently predicted cardiovascular events and mortality beyond established biomarkers. These findings support the rationale for trials of DPP3 inhibition for the treatment of high-risk patients with ASCVD.
