OLT1177 (dapansutrile) reduced infarct size by up to 67% (P<0.001 vs. vehicle) and preserved left ventricular systolic function when administered within 60 minutes after ischemia reperfusion injury.
Does OLT1177 (dapansutrile) reduce infarct size and preserve contractile function after ischemia reperfusion injury in a mouse model?
The NLRP3 inflammasome inhibitor OLT1177 (dapansutrile) significantly reduces infarct size and preserves left ventricular systolic function in a mouse model of ischemia-reperfusion injury.
Effect estimate: -67% reduction in infarct size (60 mg/kg)
p-value: p=<0.001
BACKGROUND: Activation of the NLRP3 inflammasome is a primary driver of sterile inflammation in response to myocardial ischemia reperfusion. Pharmacologic inhibitors of the NLRP3 inflammasome are being developed. We proposed that OLT1177 (dapansutrile), a novel NLRP3 inflammasome inhibitor, could preserve myocardial function after ischemia reperfusion injury in the mouse. METHODS: We used an experimental murine model of myocardial ischemia reperfusion injury through transient ligation of the left coronary artery and measured the effects of OLT1177 (6, 60, or 600 mg/kg intraperitoneal dose) on infarct size at pathology and on systolic cardiac function at echocardiography. To simulate a clinical scenario, we investigated the time window of therapeutic intervention with OLT1177 (60 mg/kg) administered 60, 120, or 180 minutes after reperfusion. RESULTS: OLT1177 was rapidly detectable in the plasma following intraperitoneal injection and had no effect on cardiac function in healthy mice. OLT1177 treatment at reperfusion showed significant dose-dependent reduction in infarct size (-36%, -67%, and -62% for 6, 60, and 600 mg/kg, respectively; P < 0.001 for linear trend, P = 0.010 vs. vehicle for 6 mg/kg, and P < 0.001 vs. vehicle for 60 and 600 mg/kg) and preserved cardiac systolic function measured as left ventricular fractional shortening at 24 hours and 7 days after injury (P = 0.015 for 6 mg/kg and P < 0.01 for 60 and 600 mg/kg). OLT1177 reduced infarct size also when given after 60 minutes of reperfusion (-71%, P < 0.001 vs. vehicle). CONCLUSION: OLT1177 (dapansutrile) limits infarct size and prevents left ventricular systolic dysfunction when given within 60 minutes following ischemia reperfusion injury in the mouse.
Toldo et al. (Tue,) conducted a other in Myocardial ischemia reperfusion injury. OLT1177 (dapansutrile) vs. Vehicle was evaluated on Infarct size at pathology and systolic cardiac function at echocardiography (-67% reduction in infarct size (60 mg/kg), p=<0.001). OLT1177 (dapansutrile) reduced infarct size by up to 67% (P<0.001 vs. vehicle) and preserved left ventricular systolic function when administered within 60 minutes after ischemia reperfusion injury.