Abstract 2671: Inhibition of Cytochrome P450 2C9 with Trans-Guidewire Therapy Dramatically Reduces Ischemia Reperfusion Injury in a Porcine Model of Acute Myocardial Infarction
Background Primary percutaneous coronary intervention (PCI) improves survival from acute myocardial infarction (MI). Reperfusion results in ischemia-reperfusion injury (IRI) and subsequent myocardial necrosis. IRI has been reduced by cytochrome P450 (CYP) 2C9 inhibitors in small animal models. Systemic delivery strategies for IRI reduction are suboptimal because of ineffective drug delivery to the infarct site.
Hypothesis Delivery of a CYP 2C9 inhibitor (chloramphenicol) via a 0.014 inch coronary guide-wire, Trans-Guidewire Therapy (TGT), could attenuate IRI in a large animal model of MI. This could reduce hemodynamic instability, myocardial dysfunction and myocardial necrosis.
Methods A porcine model of acute regional myocardial ischemia and reperfusion was achieved by coronary artery ligation after TGT wire placement. TGT feasibility was demonstrated with radiopaque contrast media and Evans blue dye. The safety of iv chloramphenicol in MI was confirmed. TGT with heparinized saline (n=5) or chloramphenicol 10 mg TGT plus 40 mg/Kg IV (n=5) was compared after 30 minutes of ischemia and 2 hours of reperfusion. Heart rate-blood pressure product (RPP) and LV ejection fraction were measured at baseline, at the end of ischemia and pre-sacrifice. Tissue samples from the infarct watershed area were analyzed for Caspase-3, an early marker of apoptosis. Tissue sections were examined for apoptosis.
Results TGT was successfully performed in all animals. Treatment with chloramphenicol resulted in a higher RPP pre-sacrifice than control animals (3720.0± 510.2 vs. 2685.7±2227.6; p=0.02) and less need for pharmacological support (1.83±1.83 vs. 7.0±5.1 arbitrary units, p=0.015). During reperfusion, LVEF in chloramphenicol-treated animals returned to near baseline (27.3%±3.8 to 43.3%±11.4, p<0.001) compared to controls (35.1±12.2% to 38.9±7.0%, p=0.52). Tissue staining of Caspase-3 was lower in the chloramphenicol group (p=0.015).
Conclusion TGT with a CYP 2C9 inhibitor prior to reperfusion improves hemodynamic parameters and left ventricular function over placebo in a porcine IRI model. There was a reduction in a biochemical marker of early apoptosis. These results could reduce myocardial injury and further improve primary PCI outcomes.