PMCID: PMC3137902 DOI: 10.1161/CIRCULATIONAHA.110.004341
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.
METHODS AND 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(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
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.
CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00113087.
Aldosterone; Angiotensins; Cohort Studies; Double-Blind Method; Female; Genotype; Growth Disorders; Heart Ventricles; Humans; Infant; Infant, Newborn; Kidney Function Tests; Male; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renin; Renin-Angiotensin System; Up-Regulation; Ventricular Function; Ventricular Remodeling
Mital, Seema; Chung, Wendy K.; Colan, Steven D.; Sleeper, Lynn A.; Manlhiot, Cedric; Arrington, Cammon B.; Cnota, James F.; Graham, Eric M.; Mitchell, Michael E.; Goldmuntz, Elizabeth; Li, Jennifer S.; Levine, Jami C.; Lee, Teresa M.; Margossian, Renee; Hsu, Daphne T.; Pediatric Heart Network Investigators; and Shirali, Girish S., "Renin-angiotensin-aldosterone genotype influences ventricular remodeling in infants with single ventricle." (2011). Manuscripts, Articles, Book Chapters and Other Papers. 928.