Early afterdepolarizations in cardiac action potentials as mixed mode oscillations due to a folded node singularity

Area of Science:

• Computational biology
• Cardiac electrophysiology
• Dynamical systems theory

Background:

• Early afterdepolarizations (EADs) are pathological cardiac voltage oscillations linked to arrhythmias.
• EADs are crucial in preclinical drug safety testing under the Comprehensive in vitro Proarrhythmia Assay (CiPA) framework.
• Previous EAD research utilized models with a single slow ion channel gating variable.

Purpose of the Study:

• To investigate EADs using dynamical systems with two slow gating variables.
• To identify a novel mechanism for EAD genesis.
• To develop a mechanism-based risk metric for computational drug proarrhythmic liability assessment.

Main Methods:

• Analysis of mixed mode oscillations in systems with two slow gating variables.
• Identification of a folded node singularity in the slow flow.
• Derivation of EAD occurrence regions using folded node and bifurcation analyses.

Main Results:

• A novel mechanism for EAD genesis involving mixed mode oscillations and a folded node singularity was identified.
• Regions of the pharmacology parameter space leading to EADs were mathematically derived.
• A normal distance to the EAD boundary was proposed as a risk metric.

Conclusions:

• The study presents a new mechanism for EADs based on dynamical systems with two slow gating variables.
• The findings offer a mechanism-based approach to computationally estimate drug proarrhythmic liability.
• This work advances the understanding of EADs in cardiac electrophysiology and drug safety evaluation.