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 the inflammasome, which triggers maturation of inflammatory cytokines. 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 % methylation of seven CpG sites in the intron region preceding exon-1 of the ASC gene. ASC methylation was inversely related to ASC mRNA (r=−.33,P<.001) and protein (r=−.464,P<.001). ASC methylation had a positive linear relationship with ejection fraction (r=.85,P<.001), quality of life (r=.83,P<.001), and six-minute walk test (r=.59,P=.023), and a negative linear relationship with depression (r=−.81,P<.001) and anxiety (r=−.75,P<.001). Higher ASC methylation was associated with a lower risk for clinical events (HR 0.16,P=.025), while higher protein (HR=1.78,P=.045) and mRNA expression (HR=1.18,P=.05) were associated with a greater risk. Conclusion 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.

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

“…Mean percent ASC methylation was 5.84 ± 0.78, which is similar to our previous results in a different HF population (10). The positive association of ASC methylation and peak V̇O 2 in this study adds a putative mechanism of epigenetic control of inflammatory gene expression contributing to decreased aerobic capacity in HF.…”

“…Previously, we reported a positive linear association between ASC methylation and 6MWT total distance in a different population of persons with HF (10). Here, we show that ASC methylation is positively related to peak V̇O 2 .…”

“…Percent methylation of 7 CpG sites in the intron region of ASC was measured as previously reported (10). In brief, genomic DNA from peripheral blood mononuclear cells (PBMCs) was bisulfite treated and amplified by PCR followed by pyrosequencing for methylation quantification.…”

“…ASC expression is controlled by epigenetic modification via methylation of a CpG island in the promoter region of exon 1 (31). Increased methylation of ASC is associated with decreased plasma IL-1β in persons with HF (10). …”

“…Higher percent ASC methylation and lower ASC mRNA expression are positively associated with the six-minute walk test (6MWT) in persons with HF (10). Although the 6MWT has been shown to be a reliable submaximal measure of functional capacity (5), a measure of maximal aerobic capacity can provide better insight into the functional capacity of an individual with HF.…”