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J Thorac Cardiovasc Surg. 2017 Nov;154(5):1703-1710.e3. doi: 10.1016/j.jtcvs.2017.06.041. Epub 2017 Jun 24.

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

Author information

1
Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
2
New England Research Institute, Watertown, Mass.
3
Children's Hospital of Los Angeles, Los Angeles, Calif.
4
Columbia University Medical Center, New York, NY.
5
Emory University, Atlanta, Ga.
6
Medical University of South Carolina, Charleston, SC.
7
Children's Hospital of Wisconsin, Milwaukee, Wis.
8
University of Utah School of Medicine, Salt Lake City, Utah.
9
Duke University Medical Center, Durham, NC.
10
University of Michigan Health, Ann Arbor, Mich.
11
Cardiovascular Data Management Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
12
Boston Children's Hospital, Boston, Mass.
13
Children's Hospital of Philadelphia, Philadelphia, Pa.
14
Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. Electronic address: seema.mital@sickkids.ca.

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

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