Abstract 2529: Aprotinin Causes Dose Dependent and Differential Effects on Myocardial Contractility, Cytokine Release and Oxidative Stress with Ischemia-Reperfusion
Background: Cardiac surgery can cause left ventricular (LV) ischemia and reperfusion (I/R), the release of cytokines such as tumor necrosis factor (TNF), and oxidative-stress causing increased myeloperoxidase (MPO). While the serine protease inhibitor aprotinin (APRO) has been commonly used in cardiac surgery, multiple pathways may be altered. Therefore, the clinical utility of APRO has been questioned. This study tested the hypothesis that APRO causes differential and dose dependent effects on LV contractility, TNF and MPO release after I/R.
Methods/Results: LV I/R injury (30 min I/ 60 min R) was induced in mice and LV contractility (maximal end-systolic elastance; Emax) was measured by conductance volumetry. Following baseline, mice were randomized to 2mL/kg APRO (n=11), 4mL/kg APRO (n=10), and Vehicle (VEH, saline, n=10). APRO doses reflected half (2 mL/kg) and full (4 mL/kg) Hammersmith doses. Plasma TNF levels (enzyme-linked flow cytometry) and LV MPO (immunochemistry) were measured and compared to reference normal controls (n=6). Emax fell from baseline (0.78±0.06 mmHg/uL*mg) following I/R, but was attenuated with 2 mL/kg APRO (Figure⇓). TNF increased from control (24±2 pg/mL) with I/R in VEH and 2 mL/kg APRO, but not with 4 mL/kg APRO. MPO increased with I/R, but was reduced with 2 mL/kg APRO compared to VEH.
Conclusions: The unique findings were:
half dose APRO reduced myocardial stunning and local oxidative stress with I/R;
full dose APRO reduced TNF release, without myocardial protective effects.
These results provide mechanistic evidence that multiple pathways are differentially and dose dependently affected by APRO in a context relevant to cardiac surgery.