title: 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.
  
  
  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.
authors.affiliation: Nell Hodgson School of Nursing, Emory University, Atlanta, Georgia.
authors.forename: Brittany
authors.initials: B
authors.lastname: Butts
authors.affiliation: Nell Hodgson School of Nursing, Emory University, Atlanta, Georgia.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Gary
authors.affiliation: Nell Hodgson School of Nursing, Emory University, Atlanta, Georgia.
authors.forename: Sandra B
authors.initials: SB
authors.lastname: Dunbar
authors.affiliation: Division of Cardiology, Stony Brook University, Stony Brook, New York. Electronic address: javed.butler@stonybrookmedicine.edu.
authors.forename: Javed
authors.initials: J
authors.lastname: Butler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053468:CARD Signaling Adaptor Proteins; D018899:CpG Islands / Q000235:genetics; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005080:Exercise Test; D005260:Female; D015870:Gene Expression; D006333:Heart Failure / Q000097:blood / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000097:blood / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics / Q000378:metabolism
chemical_list: D053468:CARD Signaling Adaptor Proteins; D016207:Cytokines; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; C402202:PYCARD protein, human; D012333:RNA, Messenger
keywords: Heart failure; epigenetic; inflammation