An Orally Available NLRP3 Inflammasome Inhibitor Prevents Western Diet-Induced Cardiac Dysfunction in Mice

Background: A diet rich in saturated fat and sugars (Western diet, WD) induces myocardial expression of the NLRP3 inflammasome and dysfunction in mice. We therefore hypothesized that a diet enriched with an orally available NLRP3 inflammasome inhibitor could prevent WD-induced cardiac dysfunction in mice. Methods: Ten-week-old CD-1 male mice were fed WD or standard diet (SD) for 8 weeks. The compound 16673-34-0, an orally active NLRP3 inhibitor, was added to the diet at a concentration of 100 mg/Kg. The plasmatic levels of the NLRP3 inflammasome inhibitor were measured. Food intake, body weight, and glucose tolerance were assessed. Cardiac systolic and diastolic functions were measured by Doppler echocardiography at baseline, 4 weeks, and 8 weeks. Results: WD induced a significant increase in body weight (+ 14%, P = 0.02), impaired glucose tolerance (+ 34%, P = 0.03), and a significant increase in isovolumetric relaxation time (+ 129%, P = 0.03) and reduction in left ventricular ejection fraction (-10%, P = 0.03), as compared to standard chow diet (SD). The treatment with NLRP3 inhibitor in the diet prevented cardiac systolic and diastolic dysfunction (P<0.05 for left ventricular ejection fraction, isovolumetric relaxation time, and myocardial performance index in WD with drug vs. WD without drug), without significant changes in heart rate and metabolic parameters. Conclusions: An orally available NLRP3 inhibitor prevented WD-induced cardiac dysfunction in obese mice.