Representing variability and transmural differences in a model of human heart failure

Area of Science:

• Cardiovascular Physiology
• Computational Biology
• Cardiac Electrophysiology

Background:

• Heart failure (HF) remodels myocyte electrophysiology, leading to ventricular arrhythmias.
• Early afterdepolarizations (EADs) and alternans (ALTs) are common manifestations of HF-induced arrhythmias.

Purpose of the Study:

• To develop a novel human ventricular cell model that incorporates experimentally observed HF data.
• To simulate the electrophysiological properties and arrhythmogenic mechanisms in failing myocytes.
• To provide a tool for predicting HF behavior at cellular, tissue, and organ levels.

Main Methods:

• Modified the O'Hara-Virág-Varró-Rudy (OVVR) model using human HF data.
• Developed a heterogeneous transmural HF-OVVR model.
• Assessed model through action potential duration, ionic current analysis, and restitution curves.

Main Results:

• The HF-OVVR model accurately replicates failing action potential properties and intracellular calcium/sodium dynamics.
• The model generates EADs and ALTs in different cell types under HF conditions.
• Simulations of blocking ionic currents (e.g., slow sodium current) showed agreement with experimental observations.

Conclusions:

• The developed HF-OVVR model elucidates cellular arrhythmogenic mechanisms in heart failure.
• This model can predict previously unobserved properties under HF conditions.
• The model serves as a valuable tool for simulating HF at multiple biological scales.