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

Abstract

Background: Heart 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 results: Stored 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.

Conclusions: Increased 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.

Keywords: Heart failure; epigenetic; inflammation.