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 breathing frequency (f_B), heart rate (HR), and heart rate variability (HRV) before, during, and after a 1 h 10% CO₂ exposure in three groups of male rats: kainic acid (KA; tonic-clonic), genetic absence epilepsy rat from Strasbourg (GAERS; absence), and Wistar controls.

Controls showed increased f_B and decreased HR during hypercapnia. KA rats exhibited blunted f_B and HR responses; GAERS displayed preserved f_B elevation with faster post-challenge normalization and intermediate HR changes. Coupling of f_B 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, whereas interictal baseline HRV did not differ among the groups.

These data support seizure-type-specific disruption of chemoreflex-autonomic integration. Extending clinical hypercapnic ventilatory response (HCVR) testing, a hypercapnic cardioventilatory response (HCCVR), that is, a combined f_B, HR, and HRV readout, may help to refine SUDEP risk stratification beyond seizure frequency and type.