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Whether a progressive pathophysiology develops and increases risk of SUDEP remains unknown. Here, we determined (a) heart rate, respiratory rate, and blood oxygen saturation (SaO<jats:sub>2<\/jats:sub>) in low\u2010risk and high\u2010risk knockout (KO) mice; and (b) whether blocking receptors for orexin, a cardiorespiratory neuromodulator, influences cardiorespiratory function mice or longevity in high\u2010risk KO mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Heart rate and SaO<jats:sub>2<\/jats:sub> were determined noninvasively with ECGenie and pulse oximetry. Respiration was determined with noninvasive airway mechanics technology. The role of orexin was determined within subject following acute treatment with a dual orexin receptor antagonist (DORA, 100\u00a0mg\/kg). The number of orexin neurons in the lateral hypothalamus was determined with immunohistochemistry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Intermittent bradycardia was more prevalent in high\u2010risk KO mice, an effect that may be the result of increased parasympathetic drive. High\u2010risk KO mice had more orexin neurons in the lateral hypothalamus. Blocking of orexin receptors differentially influenced heart rate in KO, but not wild\u2010type (WT) mice. When DORA administration increased heart rate, it also decreased heart rate variability, breathing frequency, and\/or hypopnea\u2010apnea. Blocking orexin receptors prevented the methacholine (MCh)\u2013induced increase in breathing frequency in KO mice and reduced MCh\u2010induced seizures, via a direct or indirect mechanism. DORA improved oxygen saturation in KO mice with intermittent hypoxia. Daily administration of DORA to high\u2010risk KO mice increased longevity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>High\u2010risk KO mice have a unique cardiorespiratory phenotype that is characterized by progressive changes in five interdependent endpoints. Blocking of orexin receptors attenuates some of these endpoints and increases longevity, supporting the notion that windows of opportunity for intervention exist in this preclinical SUDEP model.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.16434","type":"journal-article","created":{"date-parts":[[2020,2,7]],"date-time":"2020-02-07T05:44:12Z","timestamp":1581054252000},"page":"572-588","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Progressive cardiorespiratory dysfunction in Kv1.1 knockout mice may provide temporal biomarkers of pending sudden unexpected death in epilepsy (SUDEP): The contribution of orexin"],"prefix":"10.1111","volume":"61","author":[{"given":"Shruthi H.","family":"Iyer","sequence":"first","affiliation":[{"name":"Department of Pharmacology Creighton University School of Medicine Omaha NE 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