Abstract 11614: ASC Methylation and Outcomes in Heart Failure

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Background: Heart failure (HF) is associated with inflammation characterized by the formation of a protein complex, the inflammasome that triggers maturation of inflammatory cytokines. Inflammation in HF is associated with lower quality of life (QOL), depression, and poor outcomes. ASC, a vital component of the inflammasome, is controlled through epigenetic modification via methylation of CpG islands surrounding exon 1, and this methylation is a candidate pathway of worsening HF. The purpose of this study is to examine the relationships between ASC methylation and clinical, psychological, and QOL outcomes in HF. Methods: Stored samples from 155 HF outpatients (age 56.9±12.0 years, 64% male, 47% black, and mean LVEF 29.9±14.9) were analyzed for % methylation of seven CpG sites in the intron region preceding exon 1 of the ASC gene using pyrosequencing of bisulfite treated genomic DNA. Clinical, QOL (Kansas City Cardiomyopathy Questionnaire), and psychological (Patient Health Questionnaire [PHQ-9]) outcomes were assessed. Two-year combined clinical endpoint (death, heart transplantation, ventricular assist device implantation, or all-cause hospitalization) was analyzed. Results: Mean total ASC methylation was 5.96±0.55%. ASC methylation was inversely related to ASC mRNA (r=-.33, p<0.001) and protein (r=-.464, p<.001). ASC methylation had a positive linear relationship with ejection fraction (r=.81, p<.001) and six-minute walk distance (r=.63, p=.005). ASC methylation had a negative linear relationship with PHQ-9 scores (r=-.65, p<.001) and a positive linear relationship with QOL (r=.83, p<.001). Combined clinical endpoint occurred in 71% (N=110) of participants. Higher levels of ASC methylation were associated with lower odds of clinical endpoint (odd ratio=0.43, 95% CI .187, .997, p=.049), while higher levels of ASC protein expression were associated with higher odds (OR=1.27, 95% CI 1.04,1.54, p=.016). Conclusion: Increased methylation of CpG sites in the intron region of ASC is associated with improved clinical, psychological and QOL outcomes in HF. The associated decrease in ASC expression implicates this inflammatory mediator as a possible driver of HF outcomes, and may represent a therapeutic target.