Adrenergic receptor genotypes influence postoperative outcomes in infants in the Single-Ventricle Reconstruction Trial

Abstract

Objectives: Adrenergic receptor (ADR) genotypes have been associated with adverse outcomes in heart failure. Our objective was to evaluate the association of ADR genotypes with post-Norwood outcomes in infants with hypoplastic left heart syndrome (HLHS).

Methods: Infants with HLHS participating in the Pediatric Heart Network Single-Ventricle Reconstruction Trial underwent genotyping for 4 single-nucleotide polymorphisms in 3 ADR genes: ADRB1_231A/G, ADRB1_1165G/C, ADRB2_5318C/G, and ADRA2A_2790C/T. The association of genotype with freedom from serious adverse events (SAEs) (death, transplant, extracorporeal membrane oxygenation, cardiopulmonary resuscitation, acute shunt failure, unplanned reoperations, or necrotizing enterocolitis) during 14 months' follow-up was assessed with Cox regression and the association with post-Norwood complications was assessed with Poisson regression. Models were adjusted for clinical and surgical factors.

Results: The study included 351 eligible patients (62% male; 83% white). The mean age at Norwood procedure was 5.6 ± 3.6 days. A total of 152 patients had SAEs during 14-month follow-up including 84 deaths and 10 transplants. ADRA2A_2790CC genotype had lower SAE-free survival compared with CT/TT genotypes during follow-up (Log rank test, P = .02), and this association was independent of clinical and surgical risk factors (adjusted Cox regression, hazard ratio 1.54 [95% confidence interval 1.04, 2.30] P = .033). Post-Norwood complication rate did not differ by genotype.

Conclusions: Infants with HLHS harboring ADR genotypes that are associated with greater catecholamine release or sensitivity had lower event-free survival after staged palliation. Excess catecholamine activation may adversely affect cardiovascular adaptation after the Norwood procedure. Future studies should explore whether targeting adrenergic activation in those harboring risk genotypes can improve outcomes. (ClinicalTrials.gov number NCT00115934).

Keywords: adrenergic receptors; congenital heart surgery; genetics; hypoplastic left heart syndrome.

Figure 1

A consort flow diagram showing the outcomes in the complete and incompletely genotyped groups from patients randomized in the single ventricle reconstruction (SVR) trial.

Figure 2

Kaplan Meier survival curve showing survival free from composite primary outcome stratified by ADRA2A_2790 genotype. The shaded bands represent 95% confidence intervals. Subjects with ADRA2A_2790CC genotype had lower survival free from serious adverse events (SAE) compared to subjects with CT/TT genotypes (p=0.02).

Figure 3

Forest plot of incidence rate ratios (IRRs) of Norwood complications by genotype. The IRR is the ratio of the expected number of complications per patient per day of Norwood hospitalization in each genotype group. There were no significant differences in the IRRs of Norwood complications by genotype.

Central Message

Variations in adrenergic receptor genes influence postoperative outcomes in infants with hypoplastic left heart syndrome undergoing staged palliation. Kaplan Meier plot: Lower serious adverse event-free survival with ADRA2A_7790CC genotype (log rank test p-value=0.020).