title: 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.
abstract: The capacity of catecholamines to induce ventricular tachycardia (VT) is well documented.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors: Beth Israel Deaconess Medical Center, Boston, Massachusetts; Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors: Danilo
authors: D
authors: Bacic
authors: Beth Israel Deaconess Medical Center, Boston, Massachusetts; Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors: Juliana Saran
authors: JS
authors: Carneiro
authors: Beth Israel Deaconess Medical Center, Boston, Massachusetts; Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors: Afonso Alves
authors: AA
authors: Bento
authors: Beth Israel Deaconess Medical Center, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
authors: Bruce D
authors: BD
authors: Nearing
authors: Gilead Sciences, Inc., Foster City and Fremont, California.
authors: Sridharan
authors: S
authors: Rajamani
authors: Gilead Sciences, Inc., Foster City and Fremont, California.
authors: Luiz
authors: L
authors: Belardinelli
authors: Beth Israel Deaconess Medical Center, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts. Electronic address: rverrier@bidmc.harvard.edu.
authors: Richard L
authors: RL
authors: Verrier
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D002395:Catecholamines / Q000378:metabolism*; D004195:Disease Models, Animal; D016903:Drug Monitoring / Q000379:methods; D004562:Electrocardiography / Q000379:methods; D005424:Flecainide / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D010077:Oxazepines / Q000494:pharmacology*; D013552:Swine; D017180:Tachycardia, Ventricular / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D016896:Treatment Outcome; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology
chemical_list: D002395:Catecholamines; D010077:Oxazepines; D061567:Voltage-Gated Sodium Channel Blockers; C000624281:eleclazine; D005424:Flecainide
keywords: Catecholamines; Eleclazine; Epinephrine; Flecainide; Late sodium current; T-wave alternans; Ventricular tachycardia