Abstract 17054: Genes Associated With Inotrope Requirements in Children Undergoing Tetralogy of Fallot Repair
Introduction: Inotropes are used to prevent or treat postoperative low cardiac output syndrome. Common variants in adrenergic (ADR) signaling genes can influence inotrope response. We investigated association of both common and rare variants in ADR signaling genes with inotrope requirements in tetralogy of Fallot (TOF) patients undergoing surgical repair.
Methods: Of 276 TOF eligible patients, 120 with complete 72 hour post-operative data were analyzed. All common and rare (<1% minor allele frequency) exonic variants in 167 ADR signaling genes were extracted from whole genome sequencing data. SNP-set (Sequence) Kernel Association Test-Optimised (SKAT-O) test was used to analyze association of mutation burden in the 167 genes with inotrope requirements after adjusting for gender, reported ethnicity, age at surgery, cardiopulmonary bypass (CPB), and aortic cross clamp (ACC) times.
Results: Of 120 patients, 55 had high inotrope requirement (i.e. inotropes for >48hrs, doubling of dose, or initiation of additional inotrope). Mean CPB time was higher in the high-inotrope vs low inotrope group (128±58 vs 100±34 mins, p =0.002), as was ACC time (88±35 vs 76±25 mins, p=0.038). After adjusting for CPB and ACC time, high inotrope group had lower 24 hour mean blood pressures (p<0.01), higher plasma lactate (p=0.016), lower 24 hr urine output (p=0.001), longer ventilator duration (p=0.001) and longer ICU stay (p<0.001). After quality filtering, 689 exonic variants were identified in 129 of the 167 candidate genes; 403 were novel/rare. On preliminary analysis, variants in 9 genes were associated with high inotrope requirements (p<0.05). Three (PPP1R13B, PPP1R3F, PPP1R3A) belonged to the protein phosphatase-1 (PP1) family. PP1 is a critical negative regulator of Ca2+ cycling and contractility in cardiomyocytes and mediates inotropic response to β-adrenergic stimulation.
Conclusions: There was considerable variability in inotrope requirements in children undergoing TOF repair. Variants in PP1 gene were associated with inotrope requirements. Genomic analysis on a larger cohort is underway to identify other pharmacogenetic variants that influence inotrope response. This may guide individualization of post-operative inotrope choices in the future.
Author Disclosures: S. Lee: None. A.K. Manickaraj: None. D. Lu: None. R. Yao: None. M.A. Chan-Seng-Yue: None. P. Laussen: None. S. Schwartz: None. S. Mital: None.
- © 2016 by American Heart Association, Inc.