Cardiac‐specific Kv1.1 deficiency alters cardiomyocyte electrophysiology without modifying overall cardiac function or arrhythmia susceptibility

The leading cause of epilepsy-related mortality is sudden unexpected death in epilepsy (SUDEP), resulting from seizure-induced cardiorespiratory arrest by mechanisms that remain unresolved. Mutations in ion channel genes expressed in both brain and heart represent SUDEP risk factors because they can disrupt neural and cardiac rhythms, providing a unified explanation for seizures and lethal arrhythmias. However, the relative contributions of brain-driven mechanisms, heart-intrinsic processes and seizures to cardiac dysfunction in epilepsy remain unclear. Here, we investigated the heart-specific role of the Kcna1 gene, which encodes Kv1.1 voltage-gated potassium channel α-subunits expressed in both neurons and cardiomyocytes, where they shape action potential firing and influence seizure and arrhythmia susceptibility. We generated cardiac-specific Kcna1 conditional knockout (cKO) mice lacking Kv1.1 selectively in cardiomyocytes and assessed their cardiac function using in vitro and in vivo electrophysiology. Cardiac Kv1.1 deficiency prolonged action potentials in atrial, but not ventricular, cardiomyocytes, demonstrating a direct role for Kv1.1 in atrial repolarization. Despite these cellular effects, cKO mice exhibited normal lifespans, electrocardiographic features, heart rate variability, pacing-induced arrhythmia susceptibility, contractility, seizure susceptibility and seizure-induced mortality. Thus, while loss of cardiac Kv1.1 was sufficient to impair atrial repolarization, it did not reproduce the broader cardiac abnormalities seen in global Kcna1 knockouts. Given the higher mortality rates of global compared with neural-specific knockouts in our previous studies, cardiac Kv1.1 deficiency, while not lethal alone, may increase vulnerability to seizure-related death when combined with neural deficiency, consistent with a brain-heart dyssynergy that lowers the threshold for fatal events.