title: A computational model predicts adjunctive pharmacotherapy for cardiac safety via selective inhibition of the late cardiac Na current.
abstract: BACKGROUND
  The QT interval is a phase of the cardiac cycle that corresponds to action potential duration (APD) including cellular repolarization (T-wave). In both clinical and experimental settings, prolongation of the QT interval of the electrocardiogram (ECG) and related proarrhythmia have been so strongly associated that a prolonged QT interval is largely accepted as surrogate marker for proarrhythmia. Accordingly, drugs that prolong the QT interval are not considered for further preclinical development resulting in removal of many promising drugs from development. While reduction of drug interactions with hERG is an important goal, there are promising means to mitigate hERG block. Here, we examine one possibility and test the hypothesis that selective inhibition of the cardiac late Na current (INaL) by the novel compound GS-458967 can suppress proarrhythmic markers.
  
  
  RESULTS
  New experimental data has been used to calibrate INaLin the Soltis-Saucerman computationally based model of the rabbit ventricular action potential to study effects of GS-458967 on INaLduring the rabbit ventricular AP. We have also carried out systematic in silico tests to determine if targeted block of INaLwould suppress proarrhythmia markers in ventricular myocytes described by TRIaD: Triangulation, Reverse use dependence, beat-to-beat Instability of action potential duration, and temporal and spatial action potential duration Dispersion.
  
  
  CONCLUSIONS
  Our computer modeling approach based on experimental data, yields results that suggest that selective inhibition of INaLmodifies all TRIaD related parameters arising from acquired Long-QT Syndrome, and thereby reduced arrhythmia risk. This study reveals the potential for adjunctive pharmacotherapy via targeted block of INaLto mitigate proarrhythmia risk for drugs with significant but unintended off-target hERG blocking effects.
authors.affiliation: University of California Davis, Davis, CA, United States.
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Yang
authors.affiliation: Department of Biology, Cardiovascular Therapeutic Area, Gilead Sciences, Fremont, CA, United States.
authors.forename: Nesrine
authors.initials: N
authors.lastname: El-Bizri
authors.affiliation: Centro de Investigación e Innovación en Bioingeniería (CI2B), Universitat Politècnica de València, Valencia, Spain.
authors.forename: Lucia
authors.initials: L
authors.lastname: Romero
authors.affiliation: Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada.
authors.forename: Wayne R
authors.initials: WR
authors.lastname: Giles
authors.affiliation: Department of Biology, Cardiovascular Therapeutic Area, Gilead Sciences, Fremont, CA, United States; Amgen, Inc., 1120 Veterans Blvd, South San Francisco CA, United States.
authors.forename: Sridharan
authors.initials: S
authors.lastname: Rajamani
authors.affiliation: Department of Biology, Cardiovascular Therapeutic Area, Gilead Sciences, Fremont, CA, United States.
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.affiliation: University of California Davis, Davis, CA, United States. Electronic address: ceclancy@ucdavis.edu.
authors.forename: Colleen E
authors.initials: CE
authors.lastname: Clancy
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D064420:Drug-Related Side Effects and Adverse Reactions; D004562:Electrocardiography; D006321:Heart / Q000187:drug effects*; D006801:Humans; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D015222:Sodium Channels / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology
chemical_list: C578456:6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)(1,2,4)triazolo(4,3-a)pyridine; D000889:Anti-Arrhythmia Agents; D011725:Pyridines; D015222:Sodium Channels; D014230:Triazoles
keywords: GS-458967; Late Na current; Long-QT Syndrome; Proarrhythmia