Abstracts

Rationale:
Kv1.1 is a voltage-gated potassium channel subunit encoded by the Kcna1 gene linked to SUDEP in both mice and humans. While Kv1.1 expression was traditionally thought to be restricted to neural tissues, recent data reveals it is both present and functional in cardiomyocytes where it could play a critical role in intrinsic cardiac electrophysiology. Earlier studies investigating the role of Kv1.1 in the heart have focused on atrial tissues; however, Kv1.1 transcripts and protein are also detectable at low levels in mouse ventricular cardiomyocytes where their potential functional contribution to the heart and SUDEP risk remains unknown.
Method:
In vivo intracardiac pacing and echocardiography were performed in wildtype (WT) and Kcna1–/– (KO) mice to measure electrocardiogram (ECG) waveform characteristics, ventricular arrhythmia susceptibility, and myocardial contractility. Whole-cell patch clamp recordings were performed on isolated mouse ventricular cardiomyocytes to examine the effects of genetic and pharmacological Kv1.1 ablation. Finally, Masson’s trichrome histology and quantitative PCR analyses were used to evaluate the presence of deleterious structural and channel expression remodeling in Kv1.1-deficient ventricles.
Results:
Surface ECG recordings revealed that Kv1.1 deficiency causes long QT (QTc: +7.1%; P = 0.032), which corresponds at the cellular level to the prolonged APDs (APD90; P = 0.0039) recorded in isolated ventricular cardiomyocytes from Kcna1-/- mice. In addition, although Kcna1-/- mice exhibited normal susceptibility to inducible ventricular arrhythmias at baseline, when subjected to sympathetic challenge with isoproterenol, they showed an abnormal resistance to ventricular arrhythmias (-36%; P = 0.017). Echocardiography revealed deficits in ejection fraction (-17%; P = 0.006) and fractional shortening (-32%; P = 0.005). Notably, Kcna1-/- ventricles showed no evidence of structural or channel gene expression remodeling suggesting that the functional consequences of Kv1.1 deficiency are electrogenic in origin.
Conclusion:
This study reveals complex Kv1.1-mediated alterations in ventricular repolarization, arrhythmia susceptibility and contractility, providing the first evidence that Kv1.1 is required for normal ventricular function. Some of these deficits, such as long QT and reduced cardiac contractility could increase risk of sudden or premature death. However, other features, such as resistance to ventricular arrythmias under conditions of beta-adrenergic stimulation, suggest a cardioprotective role of Kv1.1 deficiency in the heart. Therefore, although the overall effects of Kcna1 deletion increase SUDEP susceptibility, the intrinsic cardiac-specific contribution of Kv1.1 deficiency to SUDEP risk is unclear.
Funding:
:This work was supported by grants from the National Institutes of Health (R01NS100954 and R01NS099188 to E.G.).