{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T01:03:29Z","timestamp":1780621409701,"version":"3.54.1"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T00:00:00Z","timestamp":1771632000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R03TR003869"],"award-info":[{"award-number":["R03TR003869"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,1]]},"abstract":"Abstract<\/jats:title>\n \n Rationale<\/jats:title>\n Congenital central hypoventilation syndrome (CCHS) is caused by PHOX2B gene variants, resulting in highly variable cardiac autonomic dysregulation, including abrupt sinus pauses and risk of sudden unexpected death. The relationship between age, PHOX2B genotype, and cardiac autonomic dysfunction remains unknown, and CCHS-related physiomarkers are lacking.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To assess the impact of age and genotype severity on longitudinal heart rate variability (HRV), a noninvasive measure of cardiovascular autonomic function, in CCHS.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n Longitudinal HRV measures were calculated from continuous overnight electrocardiography during polysomnography during clinical evaluation with provided artificial ventilation. PHOX2B variants were divided into moderate and severe groupings based on clinical, cellular, and in-silico PHOX2B data. Linear mixed-effects models were used to examine demographic and clinical differences in HRV by age and PHOX2B variant grouping.<\/jats:p>\n <\/jats:sec>\n \n Measurements and Main Results<\/jats:title>\n A total of 226 overnight recordings from 52 unique individuals with CCHS were included. PHOX2B variant severity was associated with decreased vagal tone, baroreflex activity, and total HRV. Increasing age was associated with reduced parasympathetic and baroreflex activity with increased sympathetic dominance.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Our findings suggest parasympathetic withdrawal with advancing age in CCHS and, potentially in response, increasing sympathetic contribution to cardiac autonomic control. Reduced baroreflex sensitivity with age, potentially due to cumulative physiologic stress, may contribute to this sympathetic dominance, offering insight into the heightened cardiovascular risk observed clinically with age. This novel relationship between PHOX2B variant severity, age, and HRV suggests that HRV may be a sensitive, easy-to-obtain physiomarker of CCHS phenotype severity and progression, providing an opportunity to predict and anticipate increasing cardioautonomic dysregulation and risk in CCHS.<\/jats:p>\n <\/jats:sec>","DOI":"10.1093\/annalsats\/aaoag027","type":"journal-article","created":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T14:21:01Z","timestamp":1771683661000},"page":"918-926","source":"Crossref","is-referenced-by-count":0,"title":["Heart rate variability: longitudinal cardioautonomic physiomarker in congenital central hypoventilation syndrome"],"prefix":"10.1093","volume":"23","author":[{"given":"Joely R","family":"Gendler","sequence":"first","affiliation":[{"name":"Center for Autonomic Medicine in Pediatrics, Department of Pediatrics, Ann & Robert H. 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