Graduate Student Southern Methodist University Dallas, Texas
This abstract is recognized by Partners Against Mortality in Epilepsy for its contribution to improving the understanding of epilepsy-related mortality
Rationale: Mutations in ion channel genes with brain-heart expression patterns have been proposed as risk factors for Sudden Unexpected Death in Epilepsy (SUDEP) since they can cause both seizures and lethal cardiac arrythmias. One such gene is Kcna1, which encodes voltage-gated Kv1.1 potassium channel α-subunits. Kcna1 global knockout (KO) mice recapitulate many features of human SUDEP including frequent generalized tonic-clonic seizures that cause cardiorespiratory dysfunction leading to sudden death in about 80% of animals. Neuron-specific Kcna1 conditional KO (cKO) mice also exhibit premature death, epilepsy, and cardiorespiratory dysregulation, but to a lesser degree than global KOs, suggesting that Kv1.1-deficiency in the heart may cause intrinsic cardiac dysfunction that increases risk of mortality. Therefore, we generated cardiac-specific Kcna1 cKO mice to test the hypothesis that Kv1.1 is required for normal intrinsic cardiac function, and that its absence contributes to cardiac phenotypes that increase risk of SUDEP. Methods: Cardiac-specific Kcna1 cKO mice were generated by crossing Myh6-Cre and floxed Kcna1 mice. Wildtype (WT), Kcna1flox/null (fl/-), and Myh6-Cre/+ (Cre) mice were used as controls. Lifespans were analyzed by Kaplan-Meier survival curves. Action potential durations (APDs) were measured in isolated cardiomyocytes using whole-cell patch clamping. Heart rate (HR) and HR variability (HRV) were measured from simultaneous electroencephalography-electrocardiography (EEG-ECG) recordings. Two-dimensional directed M-mode transthoracic echocardiography was used to measure cardiac contractility and efficiency. Surface ECG and electrograms were measured in response to intracardiac pacing to test baseline cardiac parameters and arrythmia susceptibility. Results: cKO mice exhibited normal lifespans. Whole-cell current clamp recordings revealed significantly prolonged AP durations in cKO cells (P< 0.05; n=8-20 cells/genotype). Simultaneous EEG-ECG data showed no abnormal brain activity in cKO mice, and no significant deficits in HRV parameters (n=3-6 animals/genotype). Echocardiography revealed that cKO mice had normal cardiac efficiency (ejection fraction) and contractility (fractional shortening) (n=14-22 animals/genotype). Intracardiac pacing experiments failed to detect any significant changes in arrythmia susceptibility or baseline ECG characteristics in cKO mice (n=7-12 animals/genotype). Conclusions: Cardiac-specific Kv1.1 deficiency is sufficient to cause impaired repolarization of action potentials in cardiomyocytes, which manifests as prolonged APD. However, this prolongation did not translate to significant in vivo alterations in cardiac function or arrythmia susceptibility. Together with our previous results in neuron-specific Kcna1 cKO mice, these findings confirm that cardiac phenotypes due to Kv1.1 deficiency are largely neural in origin. Therefore, increased SUDEP risk associated with the lack of Kv1.1 is likely due to factors extrinsic to the heart. Funding: Please list any funding that was received in support of this abstract.: This work was supported by NIH grant number R01NS099188 to E.G.
