title: Renin-angiotensin-aldosterone genotype influences ventricular remodeling in infants with single ventricle.
abstract: BACKGROUND
  We investigated the effect of polymorphisms in the renin-angiotensin-aldosterone system (RAAS) genes on ventricular remodeling, growth, renal function, and response to enalapril in infants with single ventricle.
  
  
  RESULTS
  Single ventricle infants enrolled in a randomized trial of enalapril were genotyped for polymorphisms in 5 genes: angiotensinogen, angiotensin-converting enzyme, angiotensin II type 1 receptor, aldosterone synthase, and chymase. Alleles associated with renin-angiotensin-aldosterone system upregulation were classified as risk alleles. Ventricular mass, volume, somatic growth, renal function using estimated glomerular filtration rate, and response to enalapril were compared between patients with ≥2 homozygous risk genotypes (high risk), and those with <2 homozygous risk genotypes (low risk) at 2 time points: before the superior cavopulmonary connection (pre-SCPC) and at age 14 months. Of 230 trial subjects, 154 were genotyped: Thirty-eight were high risk, and 116 were low risk. Ventricular mass and volume were elevated in both groups pre-SCPC. Ventricular mass and volume decreased and estimated glomerular filtration rate increased after SCPC in the low-risk (P<0.05), but not the high-risk group. These responses were independent of enalapril treatment. Weight and height z-scores were lower at baseline, and height remained lower in the high-risk group at 14 months, especially in those receiving enalapril (P<0.05).
  
  
  CONCLUSIONS
  Renin-angiotensin-aldosterone system-upregulation genotypes were associated with failure of reverse remodeling after SCPC surgery, less improvement in renal function, and impaired somatic growth, the latter especially in patients receiving enalapril. Renin-angiotensin-aldosterone system genotype may identify a high-risk subgroup of single ventricle patients who fail to fully benefit from volume-unloading surgery. Follow-up is warranted to assess long-term impact.
  
  
  BACKGROUND
  http://www.clinicaltrials.gov. Unique identifier: NCT00113087.
authors.affiliation: Division of Pediatric Cardiology Hospital for Sick Children, Toronto, Ontario, Canada. seema.mital@sickkids.ca
authors.forename: Seema
authors.initials: S
authors.lastname: Mital
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.forename: Steven D
authors.initials: SD
authors.lastname: Colan
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Sleeper
authors.forename: Cedric
authors.initials: C
authors.lastname: Manlhiot
authors.forename: Cammon B
authors.initials: CB
authors.lastname: Arrington
authors.forename: James F
authors.initials: JF
authors.lastname: Cnota
authors.forename: Eric M
authors.initials: EM
authors.lastname: Graham
authors.forename: Michael E
authors.initials: ME
authors.lastname: Mitchell
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Goldmuntz
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Li
authors.forename: Jami C
authors.initials: JC
authors.lastname: Levine
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Lee
authors.forename: Renee
authors.initials: R
authors.lastname: Margossian
authors.forename: Daphne T
authors.initials: DT
authors.lastname: Hsu
mesh_terms: D000450:Aldosterone / Q000235:genetics; D000809:Angiotensins / Q000235:genetics; D015331:Cohort Studies; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D006130:Growth Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006352:Heart Ventricles / Q000002:abnormalities* / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007677:Kidney Function Tests; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D012083:Renin / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics; D016276:Ventricular Function / Q000235:genetics*; D020257:Ventricular Remodeling / Q000235:genetics*
chemical_list: D000809:Angiotensins; D000450:Aldosterone; D007703:Peptidyl-Dipeptidase A; D012083:Renin