Arrhythmic hazard map for a 3D whole-ventricle model under multiple ion channel block

Area of Science:

• Computational biology
• Cardiovascular pharmacology
• In silico drug safety assessment

Background:

• Existing in silico models for preclinical cardiac safety testing lack predictability and usability.
• A previously developed multi-scale heart simulation accurately predicts arrhythmogenic risk for benchmark drugs.

Purpose of the Study:

• To create a comprehensive hazard map for drug-induced arrhythmia.
• To evaluate arrhythmogenic risk using simulated electrocardiogram (ECG) waveforms under various drug effects.

Main Methods:

• Utilized a multi-scale heart simulator with human cardiac electrophysiology cell models.
• Generated a five-dimensional hazard map based on 9075 simulated ECGs.
• Mapped drug effects on five key ionic currents (I_Kr, I_Na, I_Na,L, I_Ca,L, I_Ks) involved in arrhythmogenesis.

Main Results:

• The hazard map accurately predicted arrhythmogenic risk, aligning with literature assessments.
• The J-point to T-wave peak interval was identified as a superior index of arrhythmogenicity compared to the QT interval.
• The map effectively characterizes multi-channel effects on ECG waveforms.

Conclusions:

• The developed hazard map enables evaluation of drug-induced arrhythmia risk without human electrophysiological assays.
• Concentration-dependent ECG effects can be traced on the map using in vitro current assay data.
• This map serves as a novel tool for pharmaceutical research and development, improving preclinical cardiac safety testing.