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

Kelsey Paulhus; Man Si; Krystle Trosclair; Ellen Aughenbaugh; Maxine Parkinson; Nicole M Gautier-Hall; Megan Watts; Frederica Kizek; Md Shenuarin Bhuiyan; Paari Dominic; Kathryn A Hamilton; Edward Glasscock

doi:10.1101/2025.08.25.671830

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

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

Kelsey Paulhus, Man Si, Krystle Trosclair, Ellen Aughenbaugh, Maxine Parkinson, Nicole M Gautier-Hall, Megan Watts, Frederica Kizek, Md Shenuarin Bhuiyan, Paari Dominic, …

bioRxiv

Cold Spring Harbor Laboratory

08/28/2025

DOI: 10.1101/2025.08.25.671830

PMCID: PMC12407779

PMID: 40909726

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Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

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, cKOs 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.

Details

Title: Subtitle: Cardiac-specific Kv1.1 deficiency alters cardiomyocyte electrophysiology without modifying overall cardiac function or arrhythmia susceptibility
Creators: Kelsey Paulhus - Southern Methodist University
Man Si - Southern Methodist University
Krystle Trosclair - Louisiana State University Health Sciences Center Shreveport
Ellen Aughenbaugh - Southern Methodist University
Maxine Parkinson - Southern Methodist University
Nicole M Gautier-Hall - Louisiana State University Health Sciences Center Shreveport
Megan Watts - Louisiana State University Health Sciences Center Shreveport
Frederica Kizek - Southern Methodist University
Md Shenuarin Bhuiyan - Louisiana State University Health Sciences Center Shreveport
Paari Dominic - Louisiana State University Health Sciences Center Shreveport
Kathryn A Hamilton - Louisiana State University Health Sciences Center Shreveport
Edward Glasscock - Southern Methodist University
Resource Type: Preprint
Publication Details: bioRxiv
DOI: 10.1101/2025.08.25.671830
PMID: 40909726
PMCID: PMC12407779
NLM abbreviation: bioRxiv
ISSN: 2692-8205
eISSN: 2692-8205
Publisher: Cold Spring Harbor Laboratory; United States
Grant note: R01 HL145753 / NHLBI NIH HHS R01 NS129643 / NINDS NIH HHS R01 HL172970 / NHLBI NIH HHS R01 NS099188 / NINDS NIH HHS
Language: English
Date posted: 08/28/2025
Academic Unit: Cardiovascular Medicine; Internal Medicine
Record Identifier: 9984962541502771

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