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.
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.
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 LV fractional shortening (LVFS) at 24 hour 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 versus vehicle).
OLT1177 (dapansutrile), a NLRP3 inflammasome inhibitor, limits infarct size and prevents LV systolic dysfunction when given within 60 minutes following ischemia reperfusion injury in the mouse.
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1VCU Pauley Heart Center,
2Victoria Johnson Research laboratories,
3Department of Pharmacotherapy and Outcome Studies - Virginia Commonwealth University, Richmond, VA, USA.
Address for correspondence: Stefano Toldo, PhD Assistant Professor of Medicine Virginia Commonwealth University, VCU Pauley Heart Center, Box 980281, 1200 E. road St., Richmond, VA, 23298 - USA Stefano.firstname.lastname@example.org