Key result
In undiseased human ventricular muscle, IKr inhibitors (E-4031, sotalol) and the INa inhibitor mexiletine slowed electrical restitution kinetics, while IKs inhibition did not influence restitution.
Why the study?
The study aimed to investigate and compare the effects of several antiarrhythmic drugs on electrical restitution in preparations from undiseased human ventricular muscle and other mammalian species.
Do antiarrhythmic drugs modify electrical restitution kinetics in undiseased human ventricular muscle?
Do antiarrhythmic drugs modify electrical restitution kinetics in undiseased human ventricular muscle?
In undiseased human ventricular muscle, electrical restitution kinetics are slowed by IKr and INa inhibitors, suggesting that ion channel modifiers may exert antiarrhythmic effects by altering restitution.
Answers are grounded in this paper and cite their sources.
Does not support changes in antiarrhythmic selection; leaves open whether restitution modulation improves clinical outcomes.
INTRODUCTION Re entry is a basic mechanism of ventricular fibrillation, which can be elicited by extrasystolic activity, but the timing of an extrasystole can be critical. The action potential duration (APD) of an extrasystole depends on the proximity of the preceding beat, and the relation between its timing and its APD is called electrical restitution. The aim of the present work was to study and compare the effect of several antiarrhythmic drugs on restitution in preparations from undiseased human ventricular muscle, and other mammalian species. METHODS Action potentials were recorded in preparations obtained from rat, guinea pig, rabbit and dog hearts; and from undiseased human donor hearts using conventional microelectrode techniques. Preparations were stimulated with different basic cycle lengths (BCLs) ranging from 300 to 5000 ms. To study restitution, single test pulses were applied at every 20th beat while the preparation was driven at 1000 ms BCL. RESULTS Marked differences were found between the animal and human preparations regarding restitution and steady-state frequency dependent curves. In human ventricular muscle, restitution kinetics were slower in preparations with large phase 1 repolarization with shorter APDs at 1000 ms BCL compared to preparations with small phase 1. Preparations having APD longer than 300 ms at 1000 ms BCL had slower restitution kinetics than those having APD shorter than 250 ms. The selective IKr inhibitors E 4031 and sotalol increased overall APD and slowed the restitution kinetics, while IKs inhibition did not influence APD and electrical restitution. Mexiletine and nisoldipine shortened APD, but only mexiletine slowed restitution kinetics. DISCUSSION Frequency dependent APD changes, including electrical restitution, were partly determined by the APD at the BCL. Small phase 1 associated with slower restitution suggests a role of Ito in restitution. APD prolonging drugs slowed restitution, while mexiletine, a known inhibitor of INa, shortened basic APD but also slowed restitution. These results indicate that although basic APD has an important role in restitution, other transmembrane currents, such as INa or Ito, can also affect restitution kinetics. This raises the possibility that ion channel modifier drugs slowing restitution kinetics may have antiarrhythmic properties by altering restitution.
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Árpádffy‐Lovas et al. (2020) studied Undiseased human ventricular muscle. Antiarrhythmic drugs (E-4031, sotalol, L-735,821, mexiletine, nisoldipine) vs. Baseline (control conditions) was evaluated on Electrical restitution kinetics (time constant τ). In undiseased human ventricular muscle, IKr inhibitors (E-4031, sotalol) and the INa inhibitor mexiletine slowed electrical restitution kinetics, while IKs inhibition did not influence restitution.
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