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

• Type of Material: Article
• Authors: Ronand Ramroop, University of Toronto; George Manase, University of Toronto; Danny Lu, University of Toronto; Dorin Manase, University of Toronto; Shan Chen, New England Research Institutes; Richard Kim, Childrens Hosp Los Angeles; Teresa Lee, Columbia University; William Mahle, Emory University; Kimberly McHugh, Medical University of South Carolina; Mike Mitchell, Children's Hospital of Wisconsin; Martin Tristani-Firouzi, University of Utah; Stephanie Wechsler, Emory University; Nicole S Wilder, University of Michigan Health System; Victor Zak, New England Research Institutes; Myriam Lafreniere-Roula, Hospital for Sick Children; Jane W Newburger, Boston Childrens Hospital; J William Gaynor, Childrens Hospital of Philadelphia; Mark W Russell, University of Michigan Health System; Seema Mital, University of Toronto
• Language: English
• Date: 2017-11-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 The American Association for Thoracic Surgery
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jtcvs.2017.06.041
• Title of Journal or Parent Work: Journal of Thoracic and Cardiovascular Surgery
• ISSN: 0022-5223
• Volume: 154
• Issue: 5
• Start Page: 1703
• End Page: +
• Grant/Funding Information: Supported by grants HL068269, HL068270, HL068279, HL068281, HL068285, HL068288, HL068290, HL068292, HL109778, and HL085057 from the National Heart, Lung, and Blood Institute.
• Keywords: GENE POLYMORPHISMS; BETA(1)-ADRENERGIC RECEPTOR; CARDIOMYOPATHY; Cardiovascular System & Cardiology; Surgery; Life Sciences & Biomedicine; CONGENITAL HEART-DISEASE; Science & Technology; congenital heart surgery; DYSFUNCTION; genetics; Cardiac & Cardiovascular Systems; hypoplastic left heart syndrome; NORWOOD PROCEDURE; HYPERTROPHY; BLOCKADE; FIBROSIS; FAILURE; Respiratory System; adrenergic receptors
• Research Categories: Health Sciences, Medicine and Surgery

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)