ASC Methylation and Interleukin-1β Are Associated with Aerobic Capacity in Heart Failure

BACKGROUND: Aerobic capacity, as measured by peak oxygen uptake (V˙O2), is one of the most powerful predictors of prognosis in heart failure (HF). Inflammation is a key factor contributing to alterations in aerobic capacity, and interleukin (IL)-1 cytokines are implicated in this process. The adaptor protein ASC is necessary for inflammasome activation of IL-1β and IL-18. ASC expression is controlled through epigenetic modification; lower ASC methylation is associated with worse outcomes in HF. The purpose of this study is to examine the relationships between ASC methylation, IL-1β, and IL-18 with V˙O2peak in persons with HF. METHODS: This study examined the relationship between ASC methylation, IL-1β, and IL-18 with V˙O2peak in 54 stable outpatients with HF. All participants were NYHA class II or III, not engaged in an exercise program, and physically able to complete an exercise treadmill test. RESULTS: Mean V˙O2peak was 16.68 ± 4.7 mL·kg·min. V˙O2peak was positively associated with mean percent ASC methylation (r = 0.47, P = 0.001) and negatively associated with IL-1β (r = -0.38, P = 0.007). Multiple linear regression models demonstrated that V˙O2peak increased by 2.30 mL·kg·min for every 1% increase in ASC methylation and decreased by 1.91 mL·kg·min for every 1 pg·mL increase in plasma IL-1β. CONCLUSIONS: Mean percent ASC methylation and plasma IL-1β levels are associated with clinically meaningful differences in V˙O2peak in persons with HF. Inflammasome activation may play a mechanistic role in determining aerobic capacity. ASC methylation is a potentially modifiable mechanism for reducing the inflammatory response, thereby improving aerobic capacity in HF.