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Adrenergic receptor genotypes influence postoperative outcomes in infants in the Single-Ventricle Reconstruction
Ronand Ramroop1, George Manase1, Danny Lu1
1Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Insights
Adrenergic receptor genotypes impact outcomes in hypoplastic left heart syndrome (HLHS) infants post-Norwood procedure. Specific ADRA2A genotypes were linked to lower survival-free from serious adverse events.
Area of Science:
- Cardiology
- Genetics
- Pediatric Surgery
Background:
- Adrenergic receptor (ADR) genotypes are linked to adverse outcomes in heart failure.
- Infants with hypoplastic left heart syndrome (HLHS) undergo complex surgical palliation.
Purpose of the Study:
- To investigate the association between ADR genotypes and post-Norwood procedure outcomes in HLHS infants.
- To identify specific ADR gene variants that may predict adverse events after Norwood palliation.
Main Methods:
- Genotyping of 4 single-nucleotide polymorphisms in 3 ADR genes (ADRB1, ADRB2, ADRA2A) in 351 HLHS infants.
- Assessed freedom from serious adverse events (SAEs) using Cox regression over 14 months.
- Analyzed post-Norwood complications with Poisson regression, adjusting for clinical and surgical factors.
Main Results:
- The ADRA2A_2790CC genotype was associated with significantly lower SAE-free survival (P=.02), independent of other risk factors (HR 1.54, P=.033).
- No difference in post-Norwood complication rates was observed between genotypes.
- SAEs occurred in 152 patients, including 84 deaths and 10 transplants within 14 months.
Conclusions:
- HLHS infants with ADR genotypes linked to increased catecholamine activity show reduced event-free survival post-Norwood procedure.
- Excessive adrenergic activation may negatively impact cardiovascular adaptation after Norwood surgery.
- Targeting adrenergic pathways in infants with specific risk genotypes may improve outcomes.
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).
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