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.

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.

Figure 1

(a) Ventricular EDV z-scores, and (b) Ventricular mass z-scores decreased in the low-risk (black, n=116) but not in the high-risk (red, n=38) genotype groups from pre-SCPC to final study visit. High-risk, ≥ 2 homozygous risk genotypes; Low-risk, < 2 homozygous risk genotypes. *p<0.05 from pre-SCPC; # p<0.05 from low-risk group at 14 months. SCPC = superior cavopulmonary connection; EDV = end-diastolic volume

Figure 1

(a) Ventricular EDV z-scores, and (b) Ventricular mass z-scores decreased in the low-risk (black, n=116) but not in the high-risk (red, n=38) genotype groups from pre-SCPC to final study visit. High-risk, ≥ 2 homozygous risk genotypes; Low-risk, < 2 homozygous risk genotypes. *p<0.05 from pre-SCPC; # p<0.05 from low-risk group at 14 months. SCPC = superior cavopulmonary connection; EDV = end-diastolic volume

Figure 2

Difference (and 95% confidence intervals) in ventricular mass z-scores at (a) pre-SCPC and (b) final study visit between individual risk genotypes (high-risk minus no high-risk) using recessive model (*p<0.05 vs low risk genotype) showing a trend towards higher mass z-scores at 14 months in patients with high-risk genotypes with strongest association with AGTR1. (c) Linear regression model (mean± 95% confidence limits) showing incremental effect of increasing number of RAAS-upregulation genotypes on ventricular mass z-score at 14 months. 3 cases with mass z-scores outside the extreme physiologic range were excluded. AGT = Angiotensinogen; ACE = Angiotensin converting enzyme; AGTR1 = Angiotensin II type 1 receptor; CYP11B2 = Aldosterone synthase; CMA1 = Chymase; nRAAS = total number of high risk renin-angiotensin-aldosterone system genotypes; SCPC = superior cavopulmonary connection

Figure 2

Difference (and 95% confidence intervals) in ventricular mass z-scores at (a) pre-SCPC and (b) final study visit between individual risk genotypes (high-risk minus no high-risk) using recessive model (*p<0.05 vs low risk genotype) showing a trend towards higher mass z-scores at 14 months in patients with high-risk genotypes with strongest association with AGTR1. (c) Linear regression model (mean± 95% confidence limits) showing incremental effect of increasing number of RAAS-upregulation genotypes on ventricular mass z-score at 14 months. 3 cases with mass z-scores outside the extreme physiologic range were excluded. AGT = Angiotensinogen; ACE = Angiotensin converting enzyme; AGTR1 = Angiotensin II type 1 receptor; CYP11B2 = Aldosterone synthase; CMA1 = Chymase; nRAAS = total number of high risk renin-angiotensin-aldosterone system genotypes; SCPC = superior cavopulmonary connection

Figure 2

Difference (and 95% confidence intervals) in ventricular mass z-scores at (a) pre-SCPC and (b) final study visit between individual risk genotypes (high-risk minus no high-risk) using recessive model (*p<0.05 vs low risk genotype) showing a trend towards higher mass z-scores at 14 months in patients with high-risk genotypes with strongest association with AGTR1. (c) Linear regression model (mean± 95% confidence limits) showing incremental effect of increasing number of RAAS-upregulation genotypes on ventricular mass z-score at 14 months. 3 cases with mass z-scores outside the extreme physiologic range were excluded. AGT = Angiotensinogen; ACE = Angiotensin converting enzyme; AGTR1 = Angiotensin II type 1 receptor; CYP11B2 = Aldosterone synthase; CMA1 = Chymase; nRAAS = total number of high risk renin-angiotensin-aldosterone system genotypes; SCPC = superior cavopulmonary connection

Figure 3

(a) Weight, (b) height, and (c) head circumference z-scores at baseline i.e. enrollment, pre-SCPC and final study visit by genotype; Low-risk (black, n=116); high-risk (red, n=38). The offset at the different time points between the genotype groups is for better visualization of standard errors. Squares = mean value; whiskers = standard error. * p<0.05 from low risk group. SCPC = Superior cavopulmonary connection

Figure 3

(a) Weight, (b) height, and (c) head circumference z-scores at baseline i.e. enrollment, pre-SCPC and final study visit by genotype; Low-risk (black, n=116); high-risk (red, n=38). The offset at the different time points between the genotype groups is for better visualization of standard errors. Squares = mean value; whiskers = standard error. * p<0.05 from low risk group. SCPC = Superior cavopulmonary connection

Figure 3

(a) Weight, (b) height, and (c) head circumference z-scores at baseline i.e. enrollment, pre-SCPC and final study visit by genotype; Low-risk (black, n=116); high-risk (red, n=38). The offset at the different time points between the genotype groups is for better visualization of standard errors. Squares = mean value; whiskers = standard error. * p<0.05 from low risk group. SCPC = Superior cavopulmonary connection

Figure 4

This figure shows the differences in growth z-scores between the enalapril and placebo treated patients in the two risk groups (high-risk shown in red, and low-risk shown in black) at two time points - at pre-SCPC and final study visits. Data are shown as mean and 95% confidence intervals, adjusted for baseline z-scores. Mean values to the left of zero indicate lower z-scores in enalapril-treated patients i.e. placebo-beneficial; mean values to the right of zero indicate higher z-scores in the enalapril-treated patients i.e enalapril-beneficial. The interaction p values represent the differences in treatment effect between the high and low risk groups. There was no treatment effect on weight, height or head circumference in the low-risk group (black) at pre-SCPC (panel a), and at 14 months (panel b). However, high-risk patients (red) receiving enalapril had lower height z-scores at pre-SCPC, and at 14 months compared to placebo group. n=63, enalapril-treated low risk; n=53, placebo-treated low risk; n=18, enalapril-treated high risk; n=20, placebo-treated high risk. *p<0.05 enalapril vs placebo. SCPC = Superior cavopulmonary connection, WTZ = weight z-score; HTZ = height z-score; HCZ = head circumference z-score.

Figure 4

This figure shows the differences in growth z-scores between the enalapril and placebo treated patients in the two risk groups (high-risk shown in red, and low-risk shown in black) at two time points - at pre-SCPC and final study visits. Data are shown as mean and 95% confidence intervals, adjusted for baseline z-scores. Mean values to the left of zero indicate lower z-scores in enalapril-treated patients i.e. placebo-beneficial; mean values to the right of zero indicate higher z-scores in the enalapril-treated patients i.e enalapril-beneficial. The interaction p values represent the differences in treatment effect between the high and low risk groups. There was no treatment effect on weight, height or head circumference in the low-risk group (black) at pre-SCPC (panel a), and at 14 months (panel b). However, high-risk patients (red) receiving enalapril had lower height z-scores at pre-SCPC, and at 14 months compared to placebo group. n=63, enalapril-treated low risk; n=53, placebo-treated low risk; n=18, enalapril-treated high risk; n=20, placebo-treated high risk. *p<0.05 enalapril vs placebo. SCPC = Superior cavopulmonary connection, WTZ = weight z-score; HTZ = height z-score; HCZ = head circumference z-score.

Figure 5

(a) Mean change ± standard error in estimated glomerular filtration rate (eGFR) (14 months minus pre-SCPC). eGFR increased in the low-risk (black, n=85) but not in the high-risk group (red, n=26); *p<0.05 for change score from pre-SCPC. (b) The increase in eGFR in the low-risk group was independent of treatment with enalapril (red) versus placebo (black). High-risk/enalapril = 11; high-risk/placebo 15, low-risk/enalapril = 48; low risk/placebo = 37. *p<0.05 for change score from pre-SCPC. SCPC = Superior cavopulmonary connection; eGFR = estimated glomerular filtration rate

Figure 5

(a) Mean change ± standard error in estimated glomerular filtration rate (eGFR) (14 months minus pre-SCPC). eGFR increased in the low-risk (black, n=85) but not in the high-risk group (red, n=26); *p<0.05 for change score from pre-SCPC. (b) The increase in eGFR in the low-risk group was independent of treatment with enalapril (red) versus placebo (black). High-risk/enalapril = 11; high-risk/placebo 15, low-risk/enalapril = 48; low risk/placebo = 37. *p<0.05 for change score from pre-SCPC. SCPC = Superior cavopulmonary connection; eGFR = estimated glomerular filtration rate