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 four single nucleotide polymorphisms in three 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 (SAE) (death, transplant, extra-corporeal membrane oxygenation, cardiopulmonary resuscitation, acute shunt failure, unplanned re-operations, or necrotizing enterocolitis) during 14 months follow-up was assessed using Cox regression and the association with post-Norwood complications was assessed using 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. 152 patients had SAEs during 14-month follow-up including 84 deaths and 10 transplants. ADRA2A_2790CC genotype had lower SAE-free survival compared to CT/TT genotypes during follow-up (Log rank test, p=0.02) and this association was independent of clinical and surgical risk factors (Adjusted Cox regression. HR 1.54 [1.04, 2.30] p=0.033). Post-Norwood complication rate did not differ by genotype. Conclusions Infants with HLHS harboring ADR genotypes that are associated with higher 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 if targeting adrenergic activation in those harboring risk genotypes can improve outcomes. (ClinicalTrials.gov number, NCT00115934)

Advances in the Understanding of the Genetic Determinants of Congenital Heart Disease and Their Impact on Clinical Outcomes

“…A vascular endothelial growth factor A allele linked to enhanced vascular endothelial growth factor A expression was associated with preserved ventricular function and postoperative survival in patients requiring CHD surgery in infancy. Lower event‐free survival has also been associated with adrenergic signaling pathway variants that increase catecholamine release or sensitivity in patients with single‐ventricle CHD …”

“…Some of these will be related to pharmacogenomic factors, which affect a patient's biologic response to specific drugs. The studies examining the effects of renin‐angiotensin‐aldosterone system pathway genetic variation (and targeting of that pathway with angiotensin‐converting enzyme inhibition) as well those studies assessing the effect of adrenergic pathway variation on clinical outcomes in patients with CHD indicate that therapeutic approaches tailored to specific genetic profiles may help improve outcomes. This type of precision medicine approach has been applied in other medical settings and is just beginning to be considered for the care of patients with CHD.…”

“…Lower event-free survival has also been associated with adrenergic signaling pathway variants that increase catecholamine release or sensitivity in patients with single-ventricle CHD. 117 Implications for Clinical Care/Outcomes Improvement/Future Research…”

“…The impact of genetic variation on ventricular function in patients with CHD is not yet well understood. Clearly, there are common genetic variants (eg, vascular endothelial growth factor A rs833069) that can have a modest impact on ventricular function and rare genetic variants (eg, selected MYH6 variants) that can have a more significant impact . There are potentially 2 important implications of the findings to date.…”

“…While this may affect only a small percentage of patients with CHD, it may be important to consider genetic testing for concurrent dilated cardiomyopathy in a CHD patient with a decline in ventricular function that is out of proportion to the cardiac lesion or its treatment. Second, studies evaluating the impact of common genetic variation on ventricular structure and function suggest that variation in specific signaling pathways such as the renin‐angiotensin‐aldosterone system or adrenergic signaling may be suitable for pharmacologic targeting to help improve ventricular function, ventricular remodeling, and even survival in all CHD patients or in selected patients with genetic predisposition to over‐ or underactivation of those pathways. Ongoing studies examining ventricular function (in both a longitudinal and cross‐sectional manner) in CHD subjects who have had genomic characterization with exome or genome sequencing will likely identify novel mediators of ventricular function in CHD patients and help assess the relative impact of genetic variation on clinical outcomes related to ventricular performance.…”