Proarrhythmic response to sodium channel blockade. Theoretical model and numerical experiments.

Area of Science:

• Cardiac electrophysiology
• Computational modeling
• Pharmacology

Background:

• Flecainide and encainide use was halted due to increased sudden cardiac deaths.
• These drugs, along with others, affect sodium channel availability and refractoriness.
• Slowly unbinding drugs (flecainide, encainide) differ from rapidly unbinding drugs (lidocaine, moricizine).

Purpose of the Study:

• To investigate the relationship between sodium channel availability and the antiarrhythmic/proarrhythmic effects of sodium channel blockers.
• To model the impact of drug unbinding kinetics on cardiac electrical activity and arrhythmogenesis.

Main Methods:

• Computer simulation of cardiac tissue using Beeler-Reuter membrane properties.
• Modeling the effects of premature stimuli and drug-induced changes in sodium channel recovery.
• Quantifying the vulnerable window duration and its dependence on drug unbinding rates.

Main Results:

• A vulnerable window for reentrant activation was identified, sensitive to premature stimuli.
• Slowly unbinding drugs significantly delayed and prolonged this vulnerable window.
• Both antiarrhythmic and proarrhythmic effects were dependent on sodium channel availability and drug recovery kinetics.

Conclusions:

• The antiarrhythmic and proarrhythmic properties of sodium channel blockers are intrinsically linked to sodium channel availability.
• Increased antiarrhythmic efficacy (suppression of premature beats) may be accompanied by heightened proarrhythmic vulnerability.
• Drug unbinding kinetics critically influence the balance between therapeutic and adverse effects.