title: 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.
  
  
  CONCLUSIONS
  Selective cardiac late INa inhibition with GS-967 confers significant protection against catecholamine-induced VT and TWA.
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts; Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Afonso S
authors.initials: AS
authors.lastname: Alves Bento
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts; Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Danilo
authors.initials: D
authors.lastname: Bacic
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts; Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Juliana
authors.initials: J
authors.lastname: Saran Carneiro
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Nearing
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts; Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Henrique
authors.initials: H
authors.lastname: Fuller
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts; Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Fernanda A
authors.initials: FA
authors.lastname: Justo
authors.affiliation: Gilead Sciences, Inc, Foster City and Fremont, California.
authors.forename: Sridharan
authors.initials: S
authors.lastname: Rajamani
authors.affiliation: Gilead Sciences, Inc, Foster City and Fremont, California.
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts. Electronic address: rverrier@bidmc.harvard.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Verrier
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004562:Electrocardiography; D004837:Epinephrine; D006339:Heart Rate / Q000187:drug effects; D011725:Pyridines / Q000627:therapeutic use*; D013552:Swine; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: C578456:6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)(1,2,4)triazolo(4,3-a)pyridine; D011725:Pyridines; D014230:Triazoles; D004837:Epinephrine
keywords: Catecholamines; Late I(Na) inhibition; Sodium; T-wave alternans; Ventricular tachycardia