563 Effect of PHOX2B Genotype and Age on Heart Rate Variability in Pediatric Patients with Congenital Central Hypoventilation Syndrome

Abstract

Abstract Introduction Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy causing a wide array of cardiac autonomic nervous system (ANS) abnormalities (abnormal heart rate (HR) regulation, decreased HR variability (HRV), prolonged sinus pauses). CCHS is caused by mutations throughout the PHOX2B gene. Different types and locations of PHOX2B mutations have been associated with different levels of CCHS cardiac phenotype severity. We hypothesized that HRV in CCHS will be influenced by age and PHOX2B genotype. Methods PHOX2B mutation-confirmed CCHS patients in our cohort followed longitudinally with serial Holter monitoring were included. HRV measures were extracted from Holter monitoring reports and analyzed using linear mixed-effect models. Additional analyses explored which variables predicted sinus pauses and cardiac pacemaker implantation using linear and logistic regression. Only data preceding implantation of a cardiac pacemaker were included in analysis. Results 97 patients (0–18 years old) were enrolled in the study: 21 with the 20/25 genotype, 21 with the 20/26 genotype, 26 with the 20/27 genotype, 7 with genotypes ranging from 20/28-20/33, and 22 with non-polyalanine repeat expansion mutations (NPARMs). There were 965 total observations (Holters). The following HRV metrics were analyzed: min- and max-HR, longest-RR, SDNN, ASDNN5, SDANN5, and RMSDD. Statistically significant differences were observed between PHOX2B genotypes for min-HR and longest-RR (ps<0.05). Age by genotype interactions emerged such that certain metrics in HRV had different developmental trajectories by genotype (ps<0.05). Min-HR and longest-RR predicted eventual cardiac pacemaker implantation (AUCs>0.78). As for predictors of sinus pauses, different HRV metrics emerged as predictors across PHOX2B genotypes suggesting their utility in predicting cardiac pacemaker implantation dependent on genotype. Conclusion HRV in patients with CCHS is dependent on age and PHOX2B genotype, with significant differences in HRV metrics between patients with PHOX2B genotypes 20/25, 20/26, and 20/27 and the patients with 20/28-20/33 genotypes as well as those with NPARMs. Consistent with treatment guidelines, min-HR and longest-RR were predictive of eventual cardiac pacemaker implantation. Differences in the HRV metrics which predict sinus pauses as well as the overall group differences observed and trajectory-based differences may improve anticipatory management by earlier risk identification for prolonged sinus pauses in CCHS. Support (if any) None