Selective late sodium current inhibitor GS‐458967 suppresses Torsades de Pointes by mostly affecting perpetuation but not initiation of the arrhythmia

Figures

• 

  Figure 1. Overview of needle location and calculation of spatial dispersion of repolarization in the detailed mapping experiments (adapted from Dunnink et al., 2017 with permission). A total of 56 needles were inserted over six different levels of the heart, from base to apex (I to VI): in the LV, 30 needles were divided into five columns (posterior, postero‐lateral, lateral, antero‐lateral and anterior); in the RV, 18 needles were divided into three columns (posterior, lateral and anterior) and 8 needles in the septal wall (left and right sides, levels II to V, in three dogs). Dispersion of repolarization in the LV (n = 5 dogs) and in the septal wall (n = 3 dogs) was determined within adjacent electrodes of one needle (transmural dispersion, blue electrodes), one column (vertical dispersion, red electrodes), one level (horizontal dispersion, orange electrodes) and within a square of four needles (cubic dispersion, green electrodes). Maximal differences were retrieved from each orientation.

• 

  Figure 2. Late sodium current is lower in ventricular cardiomyocytes of CAVB dog (A) but its inhibition by GS967 (B and C) shortens APD and STV of repolarization (D and E). (A) The TTX‐sensitive current density was lower in ventricular cardiomyocytes isolated from CAVB dogs (n = 4) than that of SR dogs (n = 7). (D) Representative example of action potentials recorded in ventricular cardiomyocytes isolated from CAVB dog at baseline and after exposure to 300 nM GS967 (15 action potentials overlaid for both time points). (E) Relative changes in APD and STV of repolarization induced by GS967 in CAVB cardiomyocytes are respectively represented as white and red bars. The number of cardiomyocytes (isolated from 11 CAVB hearts) recorded (n) for each concentration is indicated above corresponding bars. Data are represented as mean ± SD. Unpaired t‐test: * P < 0.05 versus LV SR.

• 

  Figure 3. GS967 dose‐dependently shortens repolarization in SR dogs. Plasma levels and representative ECG and MAP recordings after administration of GS967 0.03 (A and C) and 0.1 mg·kg−1 over 5 min (B and C). For both doses, maximal electrophysiological effects were observed at peak concentrations (5 min) selective for late I Na inhibition. Data are presented as mean ± SD. Paired t‐test: * P < 0.05 versus low dose. QT, LV and RV MAPD are indicated in red on corresponding traces.

• 

  Figure 4. GS967 concentration‐dependently reduces dofetilide‐induced EADs in ventricular cardiomyocytes. In cells exhibiting reproducible dofetilide (1 μM)‐induced EADs, GS967 was superfused at 100, 300 and 1000 nM. (A) Representative example of a successful suppression of dofetilide‐induced EADs by 1000 nM GS967 in a ventricular cardiomyocyte isolated from SR dog. (B) Incidence of EADs after GS967 in the continued presence of dofetilide in ventricular cardiomyocytes isolated from 11 SR and 15 CAVB hearts. Data are presented as number of cells with remaining EADs per number of cells with dofetilide‐induced EADs.

• 

  Figure 5. GS967 completely abolishes dofetilide‐induced TdP arrhythmias in CAVB dogs. (A) Representative ECG, LV and RV MAP traces are depicted for baseline, before the first EB and TdP induced by dofetilide and after GS967 0.1 mg·kg−1 administration. (B) Incidence of arrhythmic events (sEB, mEB and TdP) after dofetilide and GS967 treatments. Data are presented as number of dogs with events per number of dogs tested. (C) AS, a surrogate parameter for arrhythmia severity, is presented as mean ± SEM. McNemar test (incidence of arrhythmia) and non‐parametric repeated measurement ANOVA (AS): # P < 0.05 versus baseline; * P < 0.05 versus dofetilide. QT, LV and RV MAPD are indicated as red numbers.

• 

  Figure 6. The reduction of spatial dispersion of repolarization underlies the in vivo antiarrhythmic effect of GS967 (0.1 mg·kg−1) in CAVB dogs. Representative example of the repolarization pattern in the LV, RV and septal wall at the different levels of the heart (from base I to apex VI) at baseline (A), before dofetilide‐induced first EB (B) and TdP (C) and following GS967 (0.1 mg·kg−1) administration (D) in a CAVB dog undergoing electrical mapping experiment. For each period, traces (with end of RT symbolized by a coloured dot and corresponding time) depict unipolar electrograms (EGMs) from the region surrounding the origin of arrhythmia, where the highest dispersion of repolarization was observed upon dofetilide administration. The suppression of TdP by GS967 was accompanied by a significant reduction of local spatial dispersion of repolarization (D). Grey regions represent low EGM amplitudes discarded from the analysis. RT, repolarization time (absolute values relative to stimulus artefact); RT diff., difference in repolarization time (relative to the first repolarized region).