title: Renin-angiotensin-aldosterone system genotype and serum BNP in a contemporary cohort of adults late after Fontan palliation.
abstract: BACKGROUND
  Adults with single ventricle physiology palliated with a Fontan circulation experience high mortality due to circulatory failure. Renin-angiotensin-aldosterone system (RAAS) genotype contributes to adverse cardiovascular outcomes in acquired heart failure. This study evaluated associations between RAAS genotype, ventricular mass and function in a contemporary cohort of adults with a Fontan circulation.
  
  
  METHODS
  This single-center prospective study included adults (n=106) seen after the Fontan operation (mean age 27±9years). Patients were genotyped for 5 pro-hypertrophic RAAS gene polymorphisms. Serum BNP, ventricular mass and function, and clinical events were compared between those with ≥2 homozygous risk genotypes ("high-risk", n=31) versus those with ≤1 homozygous risk genotypes ("low risk", n=75).
  
  
  RESULTS
  "High-risk" genotype was associated with diastolic dysfunction and higher serum BNP levels. There was no association between RAAS genotype and either ventricular mass or systolic function. During a mean follow-up duration of 9.5±7.6years, late Fontan failure occurred in 20% (n=21) of patients, including 7 deaths. Serum BNP emerged as an independent predictor of late Fontan failure (HR 1.11 [CI 1.01-1.23] for each 50unit increase in BNP, p=0.04) and death alone (HR 1.25 [CI 1.07-1.47] for each 50unit increase in BNP, p=0.006). RAAS genotype was not associated with adverse clinical events.
  
  
  CONCLUSIONS
  Fontan failure is common among adults with single ventricle physiology. RAAS genotype is not associated with increased ventricular mass but does appear to influence diastolic function late after the Fontan operation. Elevated BNP is an independent predictor of Fontan failure and mortality in adulthood.
authors.affiliation: Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada.
authors.forename: Luke J
authors.initials: LJ
authors.lastname: Burchill
authors.affiliation: Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada; Division of Pediatric Cardiology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Redington
authors.affiliation: Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada.
authors.forename: Candice K
authors.initials: CK
authors.lastname: Silversides
authors.affiliation: Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Ross
authors.affiliation: Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Jimenez-Juan
authors.affiliation: Division of Pediatric Cardiology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Division of Pediatric Cardiology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Seema
authors.initials: S
authors.lastname: Mital
authors.affiliation: Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada.
authors.forename: Erwin N
authors.initials: EN
authors.lastname: Oechslin
authors.affiliation: Division of Pediatric Cardiology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Division of Pediatric Cardiology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andreea
authors.initials: A
authors.lastname: Dragulescu
authors.affiliation: Division of Pediatric Cardiology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Cameron
authors.initials: C
authors.lastname: Slorach
authors.affiliation: Division of Pediatric Cardiology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Division of Pediatric Cardiology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Luc
authors.initials: L
authors.lastname: Mertens
authors.affiliation: Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada; Division of Pediatric Cardiology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Deparment of Medical Imaging, University Health Network, Toronto, Ontario, Canada. Electronic address: rachel.wald@uhn.ca.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Wald
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D018729:Fontan Procedure / Q000401:mortality* / Q000639:trends*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood*; D011446:Prospective Studies; D012084:Renin-Angiotensin System / Q000235:genetics*; D013997:Time Factors; D055815:Young Adult
chemical_list: D015415:Biomarkers; D020097:Natriuretic Peptide, Brain
keywords: Angiotensin-converting enzyme; Clinical genetics; Congenital heart disease; Fontan; Heart failure; Hypertrophy