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Isolation and Kv Channel Recordings in Murine Atrial and Ventricular Cardiomyocytes
Published on: March 12, 2013
Atrial proarrhythmia due to increased inward rectifier current (I(K1)) arising from KCNJ2 mutation--a simulation
Sanjay Kharche1, Clifford J Garratt, Mark R Boyett
1Biological Physics Group, The University of Manchester, UK.
Progress in Biophysics and Molecular Biology
|December 2, 2008
Summary
Increased inward rectifier potassium current (I(K1)) due to Kir2.1 mutation or other factors can prolong re-entrant wave duration. This simulation shows increased I(K1) enhances atrial susceptibility to arrhythmia by stabilizing spiral and scroll waves.
Area of Science:
- Computational Biology
- Cardiac Electrophysiology
- Molecular Cardiology
Background:
- Atrial fibrillation (AF) is associated with increased inward rectifier potassium current (I(K1)).
- This increase may result from AF-induced electrical remodeling or functional changes from the Kir2.1 V93I mutation.
Purpose of the Study:
- To investigate the mechanisms by which elevated I(K1) facilitates and perpetuates AF at cellular and tissue levels.
- To assess the impact of the Kir2.1 V93I mutation on atrial electrophysiology and arrhythmogenesis through simulations.
Main Methods:
- Modified the Courtemanche human atrial cell action potential model to include I(K1) changes from heterozygous (Het) and homozygous (Hom) Kir2.1 V93I mutations.
- Incorporated modified models into 1D, 2D, and 3D tissue models to simulate wild type (WT), Het, and Hom conditions.
- Computed restitution curves (APD, ERP, CV) and measured vulnerability to re-entry, including spiral wave lifespan and meandering.
Main Results:
- The V93I mutation abbreviated action potentials, flattened restitution curves, hyperpolarized resting membrane potential, and slowed conduction.
- Increased I(K1) reduced temporal vulnerability but increased spatial vulnerability to re-entry, elevating arrhythmogenesis.
- Spiral waves persisted in Het and Hom tissues (lifespan > 10s) compared to WT (lifespan < 3.3s).
- Increased I(K1) stabilized scroll waves in 3D models.
Conclusions:
- Elevated I(K1), whether from the Kir2.1 V93I mutation or increased maximal conductance, enhances atrial susceptibility to arrhythmia.
- This occurs by increasing the lifespan of re-entrant spiral waves and the stability of 3D scroll waves, facilitating AF initiation and maintenance.
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