Abstract 18804: Interleukin-18 Binding Protein Improves Cardiac Function in a Mouse Model of Western-diet Induced Cardiomyopathy

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Introduction: Western Diet (WD) is a risk factor for metabolic and cardiovascular diseases, and induces cardiac dysfunction in mice, through an interleukin(IL)-18 mediated mechanism. However, whether IL-18 blockade can reverse WD-induced cardiac dysfunction is unknown.

Hypothesis: We hypothesized that IL-18 blockade strategy using a recombinant IL-18 binding protein (IL-18BP) reverses cardiac dysfunction induced by WD.

Methods: C57BL mice were divided in 3 groups: 1) Standard diet (SD) for 9 weeks (N=15), 2) WD (N=8) and 3) WD+IL-18BP (N=6). IL-18BP was daily injected intraperitoneally (0.5mg/kg) after 7 weeks of WD. Caloric intake and body weight (BW) were measured. Transthoracic and pulse-wave Doppler echocardiography were performed to assess left ventricular ejection fraction (LVEF), isovolumetric relaxation time (IVRT) and myocardial performance index (MPI), at baseline, 5 and 9 weeks. Glucose was measured after 12 hours of fasting from the tail.

Results: At 9 weeks, WD-fed mice had 31% (P<0.01) higher caloric intake and higher fasting glycemia (+64% WD and +56% WD+IL-18BP vs SD; all p0.01) than SD-fed group (Figure). Compared to baseline, BW increased by 12% in the SD, by 23% in the WD and by 22% in the WD+IL18BP (all p<0.01). LVEF was unchanged for duration of the study, however, within 5 weeks of WD feeding, mice had significantly increased IVRT and MPI, indicating a cardiac diastolic dysfunction (Figure). IL-18BP started after 5 weeks of WD, significantly reduced IVRT and MPI compared to the 5 weeks time point and to the WD group not treated with IL-18BP (all p<0.01).

Conclusions: Daily treatment with IL-18BP improves cardiac function induced by WD, independent of metabolic abnormalities, proposing IL-18BP as a novel therapeutic strategy for the treatment of diastolic dysfunction.

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