Pharmacologic Inhibition of the NLRP3 Inflammasome Improves Left Ventricular Dysfunction after Severe Ischemic and Non-Ischemic Injury

Introduction: The formation of the NLRP3 inflammasome during injury to the heart amplifies the inflammatory response and mediates further damage. An inhibitor of the NLRP3 inflammasome was shown to reduce ischemia/reperfusion injury in the mouse. Hypothesis: We hypothesize that the NLRP3 inflammasome inhibitor would limit left ventricular (LV) dysfunction following severe ischemic (non-reperfused myocardial infarction [MI]) and non-ischemic (doxorubicin-induced) injury to heart. Methods: Adult male CD-1 male mice underwent permanent ligation of the left anterior descending coronary artery to induce a large non-reperfused MI (ischemic model) or injection of doxorubicin 10mg/kg to induce LV systolic dysfunction (non-ischemic model). The NLRP3 inflammasome inhibitor (16673-34-0, 100 mg/kg) or vehicle (N=6-8 per each group) were administered intraperitoneally daily for 7 days. Transthoracic echocardiography was performed to measure LV end-diastolic diameter (EDD) and LV fractional shortening (FS). We used Masson’s Trichrome stain to measure infarct size (ischemic model) or interstitial fibrosis (non-ischemic model). Results: Permanent coronary ligation led to a large non-reperfused MI and a significant increase in LVEDD and a reduction in LVFS (ischemic model). When compared with vehicle, treatment with the NLRP3 inflammasome inhibitor significantly limited LV enlargement (4.53±0.14 vs vehicle 4.95±0.04mm, P=0.006) and limited systolic dysfunction after AMI (Figure). A significant increase in interstitial fibrosis and reduction in LVFS was seen after doxorubicin treatment (non-ischemic model), and treatment with the inhibitor significantly reduced interstitial fibrosis (0.73%±0.14 vs vehicle 3.35%±0.83, P=0.001) and preserved LVFS (Figure). Conclusion: Inhibition of the NLRP3 inflammasome using a small molecule, 16673-34-0, reduces cardiac injury and limits LV systolic dysfunction following ischemic and non-ischemic injury.