Methylation of Apoptosis-Associated Speck-Like Protein With a Caspase Recruitment Domain and Outcomes in Heart Failure

• Heart failure (HF) is associated with inflammation characterized by the formation the inflammasome, which triggers maturation of inflammatory cytokines.
• Apoptosis-associated speck-like protein with a caspase recruitment domain (ASC), a vital component of the inflammasome, is controlled through epigenetic modification, which may be a candidate pathway for worsening HF.
• ASC methylation in this study was inversely related to ASC mRNA and protein.
• ASC methylation had a positive linear relationship with ejection fraction, quality of life, and 6-minute walk test, and a negative linear relationship with depression and anxiety.
• Higher ASC methylation was associated with a lower risk for clinical adverse events, whereas higher protein and mRNA expression was associated with a greater risk.

BackgroundHeart failure (HF) is associated with inflammation characterized by the formation of the inflammasome, which triggers maturation of inflammatory cytokines. Apoptosis-associated speck-like protein with a caspase recruitment domain (ASC), a vital component of the inflammasome, is controlled through epigenetic modification, which may be a candidate pathway for worsening HF. This study examined the inflammasome pathway in HF and the relationships between ASC CpG methylation and outcomes in HF.Methods and ResultsStored samples from 155 HF outpatients (ejection fraction 29.9 ± 14.9%) were analyzed for percentage methylation of 7 CpG sites in the intron region preceding exon 1 of the ASC gene. ASC methylation was inversely related to ASC mRNA (r = −0.33; P < .001) and protein (r = −0.464; P < .001). ASC methylation had a positive linear relationship with ejection fraction (r = 0.85; P < .001), quality of life (r = 0.83; P < .001), and 6-minute walk test (r = 0.59; P = .023) and a negative linear relationship with depression (r = −0.81; P < .001) and anxiety (r = −0.75; P < .001). Higher ASC methylation was associated with a lower risk for clinical events (hazard ratio [HR] 0.16; P = .025), whereas higher protein (HR = 1.78; P = .045) and mRNA expression (HR = 1.18; P = .05) were associated with a greater risk.ConclusionsIncreased methylation of CpG sites in the intron region of ASC is associated with improved 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.