Use of
ischemic postconditioning and other related cardioprotective interventions to treat patients with acute
myocardial infarction (AMI) has failed to improve outcomes in clinical trials. Because P2Y12 inhibitors are themselves postconditioning mimetics, it has been postulated that the loading dose of
platelet inhibitors routinely given to patients treated for AMI masks the anti-
infarct effect of other intended cardioprotective interventions. To further improve outcomes of patients with AMI, an intervention must be able to provide additive protection in the presence of a P2Y12
platelet inhibitor. Previous studies reported an anti-
infarct effect using a
peptide inhibitor of the pro-inflammatory caspase-1 in animal models of AMI. Herein we tested whether a pharmacologic
caspase-1 inhibitor can further limit
infarct size in open-chest, anesthetized rats treated with a P2Y12 inhibitor. One hour occlusion of a coronary branch followed by 2 hours of reperfusion was used to simulate clinical AMI and reflow. One group of rats received an intravenous bolus of 16 mg/kg of the highly selective
caspase-1 inhibitor VX-765 30 minutes prior to onset of
ischemia. A second group received a 60 µg/kg intravenous bolus of the P2Y12 inhibitor
cangrelor 10 minutes prior to reperfusion followed by 6 µg/kg/min continuous infusion. A third group received treatment with both inhibitors as above. Control animals received no treatment.
Infarct size was measured by tetrazolium
stain and volume of muscle at risk by fluorescent
microspheres. In untreated hearts, 73.7% ± 4.1% of the ischemic zone infarcted. Treatment with either
cangrelor or
VX-765 alone reduced
infarct size to 43.8% ± 2.4% and 39.6% ± 3.6% of the ischemic zone, respectively. Combining
cangrelor and
VX-765 was highly protective, resulting in only 14.0% ± 2.9%
infarction. The ability of
VX-765 to provide protection beyond that of a
platelet inhibitor alone positions it as an attractive candidate
therapy to further improve outcomes in today's patients with AMI.