Abstract 11307: Interleukin-1β and Methylation of Apoptosis Associated Speck-Like Protein Containing a Caspase Recruitment Domain Are Associated With Aerobic Capacity in Heart Failure

Abstract

Background: Aerobic capacity, as measured by peak oxygen uptake (V˙O 2 ), 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 the interleukin (IL)-1 cytokine IL-1β is implicated in this process. The adaptor protein ASC (apoptosis associated speck-like protein containing a caspase recruitment domain) is necessary for inflammasome activation of IL-1β. ASC expression is controlled through epigenetic modification, and lower ASC methylation is associated with worse outcomes in HF. Hypothesis: Peak V˙O 2 will be positively related to ASC methylation and negatively related to IL-1β in persons with HF. Methods: This cross-sectional study examined the relationship between ASC methylation and the inflammatory cytokine IL-1β with peak V˙O 2 in 54 stable outpatients with HF. All participants were NYHA class II or III, not currently engaged in an exercise program, and physically able to complete a symptom limited modified Balke exercise treadmill test. Results: Participants were 59 ± 10 years of age, 52% female, and 59% African American. Mean peak V˙O 2 was 16.68 ± 4.7 ml/kg/min. Peak V˙O 2 was positively associated with mean percent ASC methylation (r=.47, p=.001) and negatively associated with IL-1β (r=-.38, p=.007). Multiple linear regression models controlling for left ventricular ejection fraction and gender demonstrated that peak V˙O2 increased by 2.30 ml/kg/min for every 1% increase in mean 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 changes in peak V˙O 2 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. Modification of ASC expression via behavioral interventions that increase ASC methylation may improve aerobic capacity in persons with HF.