Paradoxical effects of KB-R7943 on arrhythmogenicity in a chronic myocardial infarction rabbit model
Po-Cheng Chang1, Hung-Ta Wo1, Hui-Ling Lee2
1Division of Cardiology, Department of Internal Medicine, Linko, Chang Gung Memorial Hospital, Taipei, Taiwan; Chang Gung University College of Medicine, Taoyuan, Taiwan.
Background:
Na(+)/Ca(2+) exchanger blockade has been reported to be anti-arrhythmic in different models. The effects of KB-R7943, a Na(+)/Ca(2+) exchanger blocker, on arrhythmogenesis in hearts with chronic myocardial infarction (MI) remain unclear.
Methods:
Dual voltage and intracellular Ca(2+) (Cai) optical mapping was performed in nine rabbit hearts with chronic MI and four control hearts. Electrophysiology studies including inducibility of ventricular tachyarrhythmias, ventricular fibrillation dominant frequency, action potential, Cai alternans, Cai decay, and conduction velocity were performed. The same protocol was repeated in the presence of KB-R7943 (0.5, 1, and 5μM) after the baseline studies.
Results:
KB-R7943 was effective in suppressing afterdepolarizations and spontaneous ventricular tachyarrhythmias in hearts with chronic MI. Surprisingly, KB-R7943 increased the inducibility of ventricular tachyarrhythmias in a dose-dependent manner (11%, 11%, 22%, and 56% at baseline and with 0.5, 1, and 5μM KB-R7943, respectively, p=0.02). Optical mapping analysis revealed that the underlying mechanisms of the induced ventricular tachyarrhythmias were probably spatially discordant alternans with wave breaks and rotors. Further analysis showed that KB-R7943 significantly enhanced both action potential (p=0.033) and Cai (p=0.001) alternans, prolonged Cai decay (tau value) in a dose-dependent manner (p=0.004), and caused heterogeneous conduction delay especially at peri-infarct zones during rapid burst pacing. In contrast, KB-R7943 had insignificant effects in control hearts.
Conclusions:
In this chronic MI rabbit model, KB-R7943 has contrasting effects on arrhythmogenesis, suppressing afterdepolarizations and spontaneous ventricular tachyarrhythmias, but enhancing the inducibility of tachyarrhythmias. The mechanism is probably the enhanced spatially discordant alternans because of prolonged Cai decay and heterogeneous conduction delay.
Insights
Na(+)/Ca(2+) exchanger blockade with KB-R7943 suppressed spontaneous arrhythmias but paradoxically increased inducible ventricular tachyarrhythmias in chronic myocardial infarction models. This occurred due to enhanced alternans and conduction delays, highlighting complex effects on cardiac electrophysiology.
Area of Science:
- Cardiovascular Physiology
- Cardiac Electrophysiology
- Pharmacology
Background:
- Na(+)/Ca(2+) exchanger (NCX) blockade is a potential anti-arrhythmic strategy.
- The specific effects of KB-R7943 on arrhythmogenesis in chronic myocardial infarction (MI) hearts are not well understood.
Purpose of the Study:
- To investigate the electrophysiological effects of KB-R7943 on hearts with chronic myocardial infarction.
- To determine the impact of KB-R7943 on spontaneous and inducible ventricular tachyarrhythmias.
Main Methods:
- Utilized dual voltage and intracellular Ca(2+) (Cai) optical mapping in rabbit hearts with chronic MI.
- Assessed electrophysiological parameters including arrhythmia inducibility, action potential, Cai alternans, Cai decay, and conduction velocity.
- Administered KB-R7943 at varying concentrations (0.5, 1, and 5μM) to evaluate dose-dependent effects.
Main Results:
- KB-R7943 suppressed spontaneous ventricular tachyarrhythmias and afterdepolarizations.
- Conversely, KB-R7943 significantly increased the inducibility of ventricular tachyarrhythmias in a dose-dependent manner.
- Mechanisms included enhanced spatially discordant alternans, prolonged Cai decay, and heterogeneous conduction delay, particularly in peri-infarct zones.
Conclusions:
- KB-R7943 exhibits dual effects on arrhythmogenesis in chronic MI hearts: suppressing spontaneous arrhythmias while promoting inducible ones.
- Enhanced spatially discordant alternans and conduction abnormalities are key mechanisms underlying KB-R7943-induced pro-arrhythmia.
- These findings suggest caution when considering NCX blockade for treating arrhythmias in post-MI settings.
