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Impact of Intracardiac Neurons on Cardiac Electrophysiology and Arrhythmogenesis in an Ex Vivo Langendorff System
Published on: May 22, 2018
Gap junction inhibition by heptanol increases ventricular arrhythmogenicity by reducing conduction velocity without
Gary Tse1, Jie Ming Yeo2, Vivian Tse3
1Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, P.R. China.
Insights
Gap junction inhibition with heptanol reduced cardiac conduction velocity, leading to ventricular tachycardia in mouse hearts. This highlights the role of conduction velocity and excitation wavelength in arrhythmogenesis.
Area of Science:
- Cardiovascular Physiology
- Electrophysiology
- Pharmacology
Background:
- Gap junctions are crucial for cardiac electrical impulse propagation.
- Dysfunction of gap junctions is implicated in cardiac arrhythmias.
- Heptanol is a known inhibitor of gap junction communication.
Purpose of the Study:
- To investigate the arrhythmogenic effects of the gap junction inhibitor heptanol.
- To determine the impact of heptanol on cardiac electrophysiological parameters.
- To elucidate the role of gap junction inhibition in the induction of ventricular tachycardia.
Main Methods:
- Langendorff-perfused mouse hearts were used.
- Monophasic action potentials were recorded from the left ventricular epicardium.
- Right ventricular pacing and S1S2 stimulation protocols were applied before and after heptanol treatment.
Main Results:
- Heptanol (0.05 mM) induced ventricular tachycardia in 6/12 hearts.
- Heptanol significantly increased activation latencies and reduced conduction velocity (CV).
- Action potential durations and effective refractory periods remained unchanged, but excitation wavelength (λ) was reduced.
Conclusions:
- Low-dose heptanol alone is sufficient to induce ventricular tachycardia in mouse hearts.
- Reduced CV and consequently decreased excitation wavelength (λ) are critical factors in promoting arrhythmogenic tendency.
- Inhibition of gap junctions plays a central role in the development of cardiac arrhythmias.
Abstract:
In the current study, arrhythmogenic effects of the gap junction inhibitor heptanol (0.05 mM) were examined in Langendorff-perfused mouse hearts. Monophasic action potential recordings were obtained from the left ventricular epicardium during right ventricular pacing. Regular activity was observed both prior and subsequent to application of heptanol in all of the 12 hearts studied during 8 Hz pacing. By contrast, induced ventricular tachycardia (VT) was observed after heptanol treatment in 6/12 hearts using a S1S2 protocol (Fisher's exact test; P<0.05). The arrhythmogenic effects of heptanol were associated with increased activation latencies from 13.2±0.6 to 19.4±1.3 msec (analysis of variance; P<0.001) and reduced conduction velocities (CVs) from 0.23±0.01 to 0.16±0.01 msec (analysis of variance; P<0.001) in an absence of alterations in action potential durations (ADPs) at x=90% (38.0±1.0 vs. 38.3±1.8 msec), 70% (16.8±1.0 vs. 19.5±0.9 msec), 50% (9.2±0.8 vs. 10.1±0.6 msec) or 30% (4.8±0.5 vs. 6.3±0.6 msec) repolarization (APDx) or in effective refractory period (ERPs) (39.6±1.9 vs. 40.6±3.0 msec) (all P>0.05). Consequently, excitation wavelengths (λ; CV x ERP) were reduced from 9.1±0.6 to 6.5±0.6 mm (P<0.01), however critical intervals for re‑excitation (APD90 ‑ ERP) were unaltered (‑1.1±2.4 vs. ‑2.3±1.8 msec; P>0.05). Together, these observations demonstrate for the first time, to the best of our knowledge, that inhibition of gap junctions alone using a low heptanol concentration (0.05 mM) was able to reduce CV, which alone was sufficient to permit the induction of VT using premature stimulation by reducing λ, which therefore appears central in the determination of arrhythmic tendency.
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