Selective late INa inhibition by GS-458967 exerts parallel suppression of catecholamine-induced hemodynamically significant ventricular tachycardia and T-wave alternans in an intact porcine model.

Abstract

BACKGROUND:

Catecholamines can elicit early and delayed afterdepolarizations (EADs and DADs), resulting in ventricular tachyarrhythmias.

OBJECTIVE:

As inhibition of the cardiac late sodium current (I(Na)) suppresses EADs and DADs, we examined whether GS-458967 (GS-967), a potent inhibitor of this current that is devoid of beta-adrenergic blocking action, can prevent epinephrine-induced ventricular tachycardia (VT) induction in an intact porcine model.

METHODS:

In 12 closed-chest anesthetized pigs, spontaneous VT was induced by epinephrine administration (2.0 µg/kg, intravenous, bolus over 1 minute). Effects of GS-967 (0.4 mg/kg, intravenous, infused over 30 minutes) on VT incidence, T-wave alternans (TWA) level, and hemodynamic and electrophysiologic parameters before and after epinephrine were analyzed (N = 6). Effects of vehicle control were investigated in 6 animals. TWA was measured using the Modified Moving Average method.

RESULTS:

Epinephrine elicited spontaneous hemodynamically significant nonsustained VT in all 6 pigs and increased TWA by 28-fold compared to baseline (P < .001). GS-967 reduced mean 3- to 7-beat VT incidence by 55% (from 9.5 ± 2.72 to 4.3 ± 0.76 beats/min, P = .020) and ≥8-beat VT incidence by 56% (from 1.6 ± 0.47 to 0.7 ± 0.42 beats/2 min, P = .033) and eliminated the VT-associated hypotension, with no changes in chronotropic and minimal attenuation of the inotropic responses to epinephrine. Concurrently, GS-967 at 30, 60, and 90 minutes reduced the magnitude of the epinephrine-induced surge in TWA by 56% (from 140 ± 13.2 to 62 ± 12.1 µV, P < .01), 62% (to 53 ± 8.3 µV, P < .01), and 51% (to 69 ± 14.0 µV, P < .01) (means ± SEM), respectively.

CONCLUSION:

Selective cardiac late INa inhibition with GS-967 confers significant protection against catecholamine-induced VT and TWA.

• Authors: Afonso S Alves Bento, Danilo Bacic, Juliana Saran Carneiro, Bruce D Nearing, Henrique Fuller, Fernanda A Justo, Sridharan Rajamani, Luiz Belardinelli, Richard L Verrier
• Journal: Heart rhythm (Heart Rhythm) Vol. 12 Issue 12 Pg. 2508-14 (Dec 2015) ISSN: 1556-3871 [Electronic] United States
• PMID: 26190314 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Chemical References

• 6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)(1,2,4)triazolo(4,3-a)pyridine
• Pyridines
• Triazoles
• Epinephrine

Topics

• Animals
• Blood Pressure (drug effects)
• Disease Models, Animal
• Electrocardiography
• Epinephrine
• Heart Rate (drug effects)
• Pyridines (therapeutic use)
• Swine
• Tachycardia, Ventricular (etiology, physiopathology, prevention & control)
• Triazoles (therapeutic use)