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 <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.
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, S., Chung, W. K., Colan, S. D., Sleeper, L. A., Manlhiot, C., Arrington, C. B., Cnota, J. F., Graham, E. M., Mitchell, M. E., Goldmuntz, E., Li, J. S., Levine, J. C., Lee, T. M., Margossian, R., Hsu, D. T., ., Shirali, G. S. Renin-angiotensin-aldosterone genotype influences ventricular remodeling in infants with single ventricle. Circulation 123, 2353-2362 (2011).