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Frequency-dependent antiarrhythmic drug effects on postrepolarization refractoriness and ventricular conduction time
1Cardiology Division, Stanford University School of Medicine, California.
Insights
Class I antiarrhythmic drugs affect re-entry circuits differently. Mexiletine and quinidine increased the effective refractory period/action potential duration ratio, with combination therapy showing greater effects, while lidocaine had minimal impact.
Area of Science:
- Cardiovascular Pharmacology
- Electrophysiology
Background:
- Re-entry arrhythmias are driven by conduction time (CT) and effective refractory period (ERP), relative to action potential duration (APD).
- Class I antiarrhythmic agents are commonly used to manage these arrhythmias.
Purpose of the Study:
- To compare the effects of lidocaine, mexiletine, quinidine, and a mexiletine/quinidine combination on APD, ERP, ERP/APD ratio, and interventricular CT.
- To assess the frequency-dependent effects of these agents on electrophysiological parameters.
Main Methods:
- In vivo canine heart model with 26 subjects.
- Measurements of APD and ERP at the left ventricle using a modified contact electrode technique.
- Assessment of interventricular CT from right ventricular pacing to left ventricular activation.
- Evaluation across multiple steady-state cycle lengths (600-250 msec).
Main Results:
- Lidocaine showed no significant changes in APD, ERP, or ERP/APD ratio.
- Mexiletine and quinidine increased the ERP/APD ratio, with greater effects at shorter cycle lengths.
- The mexiletine/quinidine combination significantly increased the ERP/APD ratio more than individual drugs.
- Interventricular CT increased with quinidine but not with mexiletine or lidocaine; combination therapy did not further slow conduction compared to quinidine alone.
Conclusions:
- Mexiletine and quinidine differentially affect electrophysiological parameters crucial for re-entry arrhythmia circuits.
- The combination of mexiletine and quinidine demonstrates enhanced effects on the ERP/APD ratio.
- Drug effects on ERP/APD ratio and CT are not always quantitatively similar, despite both relating to sodium channel conductance.
Abstract:
Both conduction time (CT) and effective refractory period (ERP), absolute and relative to action potential duration (APD), are major determinants of re-entry arrhythmia circuits. We compared the effects of 3 commonly used class I antiarrhythmic agents, lidocaine, mexiletine and quinidine, and of the combination of the latter 2, on APD, ERP, ERP/APD ratio and interventricular CT in 26 in vivo canine hearts. To assess also the frequency dependence of these effects, each measurement was made at multiple steady-state cycle lengths ranging from 600 to 250 msec. A modified contact electrode technique was used to measure both APD and ERP simultaneously and at the same left ventricular site. Interventricular CT was measured as the interval from the stimulus of right ventricular paced beats to the upstroke of the ensuing left ventricular action potential. Lidocaine did not change APD, ERP and ERP/APD ratio significantly at any basic cycle length. In contrast, both mexiletine and quinidine increased the ERP/APD ratio, with progressively greater effects toward shorter cycle lengths. The quinidine/mexiletine combination increased the ERP/APD ratio significantly more than either drug alone (cycle length 350 msec: 8.3 +/- 2.2% quinidine; 17.6 +/- 7.0% mexiletine; 35.3 +/- 9.6% mexiletine/quinidine combination, P less than .01 vs. quinidine, P less than .05 vs. mexiletine). CT increased only with quinidine but not with mexiletine or lidocaine. Combination of mexiletine and quinidine caused no further slowing of conduction as compared to quinidine alone. Thus, although both ERP/APD ratio and CT are related to sodium channel conductance, drug effect on one parameter does not necessarily imply quantitatively similar effects on the other.(ABSTRACT TRUNCATED AT 250 WORDS)