Eleclazine, an inhibitor of the cardiac late sodium current, is superior to flecainide in suppressing catecholamine-induced ventricular tachycardia and T-wave alternans in an intact porcine model

Heart Rhythm. 2017 Mar;14(3):448-454. doi: 10.1016/j.hrthm.2016.10.021. Epub 2016 Oct 21.

Abstract

Background: The capacity of catecholamines to induce ventricular tachycardia (VT) is well documented.

Objective: The effectiveness of the novel cardiac late sodium inhibitor eleclazine in suppressing catecholamine-induced VT in a large animal model was compared with that of flecainide.

Methods: In 13 closed-chest anesthetized Yorkshire pigs, spontaneous VT and surges in T-wave alternans (TWA) level measured using the Modified Moving Average method were induced by epinephrine (2.0 µg/kg, i.v., bolus over 1 minute). Effects of eleclazine (0.3 mg/kg, i.v., infused over 15 minutes; n = 6) or flecainide (1 mg/kg, i.v., bolus over 2 minutes followed by 1 mg/kg/hr, i.v., for 1 hour; n = 7) on VT incidence and TWA level were measured from right intraventricular electrogram recordings.

Results: Epinephrine reproducibly elicited hemodynamically significant spontaneous VT in all 13 pigs and increased TWA level by 33-fold compared to baseline (P < .001). Eleclazine reduced the incidence of epinephrine-induced ventricular premature beats and couplets by 51% (from 31.3 ± 1.91 to 15.2 ± 5.08 episodes; P = .038) and the incidence of 3- to 7-beat VT by 56% (from 10.8 ± 3.45 to 4.7 ± 3.12 episodes; P = .004). Concurrently, the drug reduced the peak epinephrine-induced TWA level by 64% (from 217 ± 22.2 to 78 ± 15.3 µV; P < .001). Flecainide also reduced the incidence of epinephrine-induced ventricular premature beats and couplets by 53% (from 40.4 ± 6.37 to 19.0 ± 2.73 episodes; P = .024) but did not affect the incidence of VT (from 15.0 ± 3.08 to 11.6 ± 2.93 episodes; P = .29) or the peak TWA level (from 207 ± 30.6 to 172 ± 26.2 µV; P = .34).

Conclusion: Selective inhibition of cardiac late sodium current with eleclazine is more effective than flecainide in reducing catecholamine-induced VT and TWA in an intact porcine model.

Keywords: Catecholamines; Eleclazine; Epinephrine; Flecainide; Late sodium current; T-wave alternans; Ventricular tachycardia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Animals
  • Catecholamines / metabolism*
  • Disease Models, Animal
  • Drug Monitoring / methods
  • Electrocardiography / methods
  • Flecainide / pharmacology*
  • Hemodynamics / drug effects
  • Oxazepines / pharmacology*
  • Swine
  • Tachycardia, Ventricular* / drug therapy
  • Tachycardia, Ventricular* / metabolism
  • Tachycardia, Ventricular* / physiopathology
  • Treatment Outcome
  • Voltage-Gated Sodium Channel Blockers / pharmacology

Substances

  • Catecholamines
  • Oxazepines
  • Voltage-Gated Sodium Channel Blockers
  • eleclazine
  • Flecainide