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Proarrhythmic response to sodium channel blockade. Theoretical model and numerical experiments
C F Starmer1, A A Lastra, V V Nesterenko
1Department of Medicine, Duke University Medical Center, Durham, N.C. 27710.
Background:
The use of flecainide and encainide was terminated in the Cardiac Arrhythmia Suppression Trial because of an excess of sudden cardiac deaths in the active treatment group. Such events might arise from reentrant rhythms initiated by premature stimulation in the presence of anisotropic sodium channel availability. Drugs that bind to sodium channels increase the functional dispersion of refractoriness by slowing (a result of the drug-unbinding process) the transition from an inexcitable state to an excitable state. It is interesting that encainide and flecainide unbind slowly (15-20 seconds), whereas lidocaine and moricizine unbind rapidly (0.2-1.3 seconds).
Methods And Results:
With a computer representation of a cable with Beeler-Reuter membrane properties, we found a small (6 msec) vulnerable window that occurred 338 msec after the last drive stimulus. Premature stimuli falling within the vulnerable window resulted in unidirectional block and reentrant activation. In the presence of a slowly unbinding drug, the window was delayed an additional 341 msec, and its duration was extended to 38 msec. The delay (antiarrhythmic effect) before the onset of the vulnerable window and its duration (proarrhythmic effect) were both dependent on the sodium channel availability and the recovery process. Both effects were also prolonged when sodium channel availability was reduced by membrane depolarization. Defining the proarrhythmic potential as the duration of the vulnerable window, we found that hypothetical use-dependent class I drugs have a greater proarrhythmic potential than non-use-dependent drugs.
Conclusions:
The antiarrhythmic and proarrhythmic properties of pure sodium channel antagonists are both dependent on sodium channel availability. Consequently, the price for increased antiarrhythmic efficacy (suppressed premature ventricular contractions) is an increased proarrhythmic vulnerability to unsuppressed premature ventricular contractions.
Insights
Slowly unbinding sodium channel blockers, like flecainide, increase proarrhythmic potential by prolonging the vulnerable window. This antiarrhythmic drug effect comes with increased risk of cardiac arrhythmias.
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.