INTERLEUKIN-18 AS A THERAPEUTIC TARGET FOR WESTERN DIET-INDUCED CARDIOMYOPATHY

A diet high in saturated fats and sugars (Western diet-WD) promotes obesity and left ventricular dysfunction in the mouse, which is, at least in part, mediated by pro-inflammatory cytokine Interleukin-18 (IL-18). Therefore, we hypothesized that a blocking recombinant-murine IL-18 binding protein (IL-18BP) would rescue cardiac function in WD-fed mice.

In this 9-week study, 10-week-old adult C57BL/6J mice were assigned to standard diet (SD) or a WD. After 7 weeks of WD feeding, the mice were assigned to two groups: WD+IL-18BP (0.5 mg/kg daily, intraperitoneal injections) or WD control for the last 2 weeks of the study. Food intake, body weight, and glucose tolerance were assessed. Cardiac systolic and diastolic function were measured by Doppler echocardiography at baseline, 5 weeks, and 9 weeks. IL-18 plasma levels were quantified with ELISA.

WD induced a significant increase in body weight, significantly worsened glucose tolerance, and significantly increased (worsening) in diastolic function (isovolumetric relaxation time -IRT- and myocardial performance index -MPI-) compared to SD. Rescue with IL-18BP in WD-fed mice resulted in a significant improvement in IRT and MPI, without significant changes in food intake, weight gain, or glucose tolerance.

IL-18BP rescued cardiac function in mice with WD-induced diastolic dysfunction, independent of weight gain and glucose tolerance. These results confirm the central and independent role of IL-18 in cardiac dysfunction associated with diet-induced obesity.