title: Selective late sodium current blockade with GS-458967 markedly reduces ischemia-induced atrial and ventricular repolarization alternans and ECG heterogeneity.
abstract: BACKGROUND
  Ischemic heart disease is associated with dual risk for atrial and ventricular arrhythmias.
  
  
  OBJECTIVE
  We examined whether selectively targeting late sodium channel current (INa) with GS-458967 (hereafter GS967) can reduce cardiac electrical instability and compared its effects to a clinically relevant dose of flecainide.
  
  
  METHODS
  Electrode catheters were positioned on the left atrial appendage and left ventricle of anesthetized pigs to monitor repolarization alternans and electrocardiographic heterogeneity before and during left circumflex coronary artery stenosis (75% flow reduction) before and after GS967 (0.4 mg/kg, intravenously [IV]) or flecainide (1 mg/kg, IV, bolus over 2 minutes followed by 1 mg/(kg·h), IV, for 1 hour) administration.
  
  
  RESULTS
  Left circumflex coronary artery stenosis increased atrial repolarization alternans by 520% (from 9.4 ± 1.2 to 58.3 ± 11.3 μV; P = .029) and T-wave alternans by 1038% (from 30.7 ± 8.2 to 349.3 ± 103.8 μV; P = .049). GS967 prevented ischemia-induced increases in alternans in the left atrium (19.3 ± 5.6 μV vs 58.3 ± 11.3 μV; P = .023) and left ventricle (217.9 ± 95.8 μV vs 349.3 ± 103.8 μV; P < .001) (n = 7). GS967 reduced ischemia-induced increases in depolarization heterogeneity (atrium: from 45% to 28%; ventricle: from 92% to 51%) and repolarization heterogeneity (atrium: 43% to 23%; ventricle: 137% to 91%). GS967 did not alter heart rate, arterial blood pressure, PR and QT intervals, or QRS duration, but it mildly decreased contractility (left ventricular dP/dt) during ischemia, which was consistent with late INa inhibition. Flecainide (n = 7) amplified ischemia-induced increase in atrial and ventricular repolarization alternans, electrocardiographic heterogeneity, and ventricular fibrillation incidence.
  
  
  CONCLUSIONS
  Selective late INa inhibition with GS967 exerts potent protective effects against ischemia-induced depolarization and repolarization abnormalities in both atria and ventricles.
authors: Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors: Rodolfo
authors: R
authors: Bonatti
authors: Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors: Ana Flavia Garcia
authors: AF
authors: Silva
authors: Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors: Julio Americo Pereira
authors: JA
authors: Batatinha
authors: Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors: Lucas F
authors: LF
authors: Sobrado
authors: Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors: Ananda Dianni
authors: AD
authors: Machado
authors: Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors: Bruno B
authors: BB
authors: Varone
authors: Beth Israel Deaconess Medical Center, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
authors: Bruce D
authors: BD
authors: Nearing
authors: Gilead Sciences, Foster City, 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: D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D023921:Coronary Stenosis / Q000150:complications* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D007275:Injections, Intravenous; D008297:Male; D011725:Pyridines / Q000008:administration & dosage*; D026941:Sodium Channel Blockers / Q000008:administration & dosage; D013552:Swine; D013997:Time Factors; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage*; D014693:Ventricular Fibrillation / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology
chemical_list: C578456:6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)(1,2,4)triazolo(4,3-a)pyridine; D011725:Pyridines; D026941:Sodium Channel Blockers; D014230:Triazoles
keywords: Antiarrhythmic drugs; Atrial fibrillation; Atrial ischemia; Depolarization; Heterogeneity; Late I(Na); Repolarization; Ventricular fibrillation; Ventricular ischemia