Inhibition of the cardiac late sodium current with eleclazine protects against ischemia-induced vulnerability to atrial fibrillation and reduces atrial and ventricular repolarization abnormalities in the absence and presence of concurrent adrenergic stimulation.

Abstract

BACKGROUND:

Myocardial ischemia carries dual risk for initiating atrial and ventricular arrhythmias that can be exacerbated by adrenergic stimulation.

OBJECTIVE:

The purpose of this study was to investigate whether selective inhibition of the cardiac late sodium current (INa) with eleclazine decreases susceptibility to ischemia-induced atrial fibrillation (AF) and atrial and ventricular repolarization abnormalities before and after epinephrine infusion.

METHODS:

In chloralose-anesthetized, open-chest, male Yorkshire pigs (n = 12), atrial and ventricular ischemia was induced by partial occlusion of the left circumflex coronary artery proximal segment to reduce flow by 75%. Epinephrine (0.5 µg/kg IV bolus over 1 minute; n = 6) was infused before and at 2 hours after eleclazine (0.9 mg/kg IV bolus over 15 minutes).

RESULTS:

Left circumflex coronary artery occlusion significantly increased ventricular dispersion of repolarization (T-wave alternans [TWA] by 861%, T-wave heterogeneity by 286%, Tpeak-Tend interval by 74%) and atrial repolarization alternans (TWAa) by 2850% and lowered AF threshold by 65%. Eleclazine reduced the ischemia-induced surge in TWA by 81% (P = .007), T-wave heterogeneity by 23% (P = .035), and Tpeak-Tend by 28% (P = .014), suppressed the ischemia-induced surge in atrial TWAa by 64% (P = .002), and reduced the ischemia-induced fall in AF threshold to 20%. It shortened baseline QT interval by 6% (P <.001), JT interval by 8% (P <.001), and atrial action potential duration (PTa) by 8% (P = .002). Similar beneficial effects of eleclazine were observed after epinephrine infusion without reducing contractility (P = .054).

CONCLUSION:

Selective inhibition of cardiac late INa with eleclazine confers dual protection against vulnerability to ischemia-induced AF and reduces atrial and ventricular repolarization abnormalities before and during adrenergic stimulation without negative inotropic effects.

• Authors: Fernanda Justo, Henrique Fuller, Bruce D Nearing, Sridharan Rajamani, Luiz Belardinelli, Richard L Verrier
• Journal: Heart rhythm (Heart Rhythm) Vol. 13 Issue 9 Pg. 1860-7 (09 2016) ISSN: 1556-3871 [Electronic] United States
• PMID: 27317981 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Chemical References

• Adrenergic Agents
• Oxazepines
• Sodium Channel Blockers
• Sodium Channels
• eleclazine
• Epinephrine

Topics

• Adrenergic Agents (pharmacology)
• Animals
• Arrhythmias, Cardiac (diagnosis, etiology, physiopathology, prevention & control)
• Atrial Fibrillation (diagnosis, etiology, physiopathology, prevention & control)
• Disease Models, Animal
• Disease Susceptibility (therapy)
• Electrocardiography
• Epinephrine (pharmacology)
• Male
• Myocardial Ischemia (complications, physiopathology)
• Oxazepines (pharmacology, therapeutic use)
• Sodium Channel Blockers (pharmacology, therapeutic use)
• Sodium Channels (drug effects)
• Swine