Effect of epileptogenesis on hypercapnic cardioventilatory response in kainic acid rats

Cardioventilatory failure is the leading mechanism proposed to underlie sudden unexpected death in epilepsy (SUDEP), which occurs predominantly at night in patients with generalized tonic-clonic seizures. Interictal hypercapnic cardioventilatory responses are suggested to be involved, as they are ablated in chronically epileptic kainic acid (KA) rats, a temporal lobe epilepsy model with focal to bilateral tonic-clonic seizures. However, how this impairment emerges during epileptogenesis and whether it is influenced by day/night period remain unclear. Here, we aimed to investigate the progress of hypercapnic cardioventilatory responses through the epileptogenesis of KA rats and whether it is affected by day or night.

Ventilatory or breathing frequency (f_B) and heart rate (HR) were measured before, during, and after a 1-h exposure to acute hypercapnia (10% CO₂) using photoplethysmography in KA and healthy rats. Measurements were performed monthly for 6 months, with additional nocturnal hypercapnia recordings at month 6 to assess day/night modulation. To control for repeated CO₂ exposure, an independent cohort of age-matched KA and healthy rats underwent a single hypercapnia exposure at month 6.

In healthy rats, cardioventilatory responses to hypercapnia remained stable over time, with increased f_B and reduced HR. Conversely, KA rats displayed an abrupt blunting of the f_B response at month 4, followed by blunting of the HR response at month 6. Correlation analyses revealed a loss of correlation between f_B and HR following KA injection, which reemerged when the cardioventilatory response to CO₂ was fully ablated. No association was observed between seizure severity and cardioventilatory impairment. KA rats displayed similar deficits regardless of CO₂ exposure frequency, and no day-night differences were detected in either group.

These findings indicate that cardioventilatory responses are decreased during epileptogenesis in the KA model, suggesting their potential utility for evaluating SUDEP risk.