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Published on: December 2, 2016
Renin-angiotensin-aldosterone genotype influences ventricular remodeling in infants with single ventricle
Seema Mital1, Wendy K Chung, Steven D Colan
1Division of Pediatric Cardiology Hospital for Sick Children, Toronto, Ontario, Canada. seema.mital@sickkids.ca
Insights
Genetic variations in the renin-angiotensin-aldosterone system (RAAS) impact single ventricle infant outcomes. High-risk RAAS genotypes are linked to poor ventricular remodeling and growth, especially with enalapril.
Area of Science:
- Cardiovascular Genetics
- Pediatric Cardiology
- Renal Physiology
Background:
- Single ventricle (SV) physiology presents complex challenges in pediatric cardiology.
- The renin-angiotensin-aldosterone system (RAAS) plays a crucial role in cardiovascular and renal regulation.
- Investigating genetic predispositions in SV patients is vital for understanding treatment responses.
Purpose of the Study:
- To examine the influence of RAAS gene polymorphisms on ventricular remodeling, growth, and renal function in infants with SV.
- To assess how these genetic variations affect the response to enalapril treatment.
- To identify potential genetic markers for stratifying SV patient risk.
Main Methods:
- Genotyping of 5 RAAS genes (angiotensinogen, ACE, AT1R, aldosterone synthase, chymase) in SV infants from a randomized enalapril trial.
- Classification of alleles into risk and non-risk categories based on RAAS upregulation.
- Comparison of ventricular mass/volume, somatic growth (height/weight z-scores), and estimated glomerular filtration rate (eGFR) between high-risk (≥2 homozygous risk genotypes) and low-risk groups pre- and post-superior cavopulmonary connection (SCPC).
Main Results:
- Infants with high-risk RAAS genotypes showed impaired reverse remodeling and no significant improvement in eGFR after SCPC surgery compared to low-risk infants.
- High-risk infants exhibited lower baseline weight and height z-scores, with persistent height deficits at 14 months, particularly those on enalapril.
- Ventricular remodeling and renal function changes post-SCPC were independent of enalapril treatment in this cohort.
Conclusions:
- RAAS-upregulating genotypes are associated with adverse outcomes in SV patients, including failed reverse remodeling, diminished renal function improvement, and impaired somatic growth.
- Genetic profiling of the RAAS may identify SV infants who are less likely to benefit from volume-unloading surgery.
- Further follow-up is necessary to determine the long-term clinical implications of these genetic associations.
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.
