Seizure-Type–Specific Disruption of Hypercapnic Cardioventilatory Responses in Epilepsy Models

Sudden Unexpected Death in Epilepsy (SUDEP) is linked to respiratory and autonomic failure with post-ictal periods of prolonged hypercapnia indicative of impaired central chemoreception. Yet how interictal hypercapnic cardioventilatory responses vary by seizure phenotype is unclear. We aimed to determine whether central chemoreception and autonomic regulation differ across epilepsy phenotypes during a standardized CO₂ challenge. We hypothesized that rats with chronic generalized tonic–clonic seizures would show impaired hypercapnic cardioventilatory and autonomic responses compared with rats with generalized absence seizures and healthy controls. We measured ventilatory frequency (fB), heart rate (HR), and heart-rate variability (HRV) before, during, and after a 1hour 10 % CO₂ exposure in 3 groups of male rats: kainic acid (KA; tonic–clonic), GAERS (absence), and Wistar controls. Controls showed increased fB and decreased HR during hypercapnia. KA rats exhibited blunted fB and HR responses; GAERS displayed preserved fB elevation with faster post-challenge normalization and intermediate HR changes. Coupling of fB and HR collapsed during CO₂ in both epilepsy groups and re-emerged in recovery. In KA rats, stage 3–4 seizure burden positively correlated with HR during hypercapnia. HRV reactivity to hypercapnia was robust in controls, attenuated in GAERS, and largely absent in KA, while interictal baseline HRV did not differ among groups. These data support seizure-type–specific disruption of chemoreflex–autonomic integration. Extending clinical hypercapnic ventilatory response (HCVR) testing, a hypercapnic cardioventilatory response (HCCVR), i.e. a combined fB, HR, and HRV readout may help to refine SUDEP risk stratification beyond seizure frequency and type.