Abstract 13208: Deletion of the Type I Interleukin-1 Receptor Prevents the Development of Cardiomyopathy Associated With Aging in Mice

Abstract

Background: Aging is associated with metabolic and structural changes causing heart failure with preserved ejection fraction (HFpEF). Interleukin-1 (IL-1) is a pro-inflammatory cytokine involved in aging-related inflammation. We sought to determine whether IL-1 mediates aging-related changes in the heart as seen in HFpEF. Hypothesis: We hypothesize that mice with genetic deletion of IL-1RI, not responsive to IL-1β, would be protected from age-associated cardiac dysfunction. Methods: We studied age-matched young (4-month-old), middle-aged (14-month-old) and old (23-month-old) wild-type (WT) C57BL/6J and IL-1 receptor type I deficient (IL1RI-KO) male mice. Echocardiography was used to left ventricular (LV) dimensions and systolic/diastolic function, and a pressure-transducer was used to measure the LV end-diastolic pressure. Picrosirius red stain was used to assess for myocardial interstitial fibrosis (MIF) at pathology. Results: WT and IL-1RIKO mice showed a normal cardiac phenotype at young age, without any differences in between the two groups. With aging, the WT mice developed LV concentric hypertrophy (as measured by a significant increase in LV mass [+42%, P<0.01] and relative wall thickness [+34%, P<0.01]), whereas the aging IL-1RI-KO mice did not (Figure 1a,b). With aging the WT mice also developed diastolic dysfunction (as measured by a significant increase in isovolumetric relaxation time [+148%, P<0.01] and a significantly higher LV end diastolic pressure [+174%, P<0.01]), whereas the aging IL1RI-KO did not (Figure 1c,d). With aging WT mice showed a significant increase in MIF (+124%, P<0.01) at cardiac pathology, whereas the aging IL-1RI-KO did not (Figure 1e). Conclusions: Genetically-modified mice lacking the IL-1RI receptor, not responsive to IL-1, are protected from aging-related LV hypertrophy, fibrosis and diastolic dysfunction. These data support a central role of IL-1 in the pathophysiology of aging-related HFpEF.