The INaL inhibitor GS967 decreased repolarization abnormalities and prevented triggered activity in murine and human iPSC-derived cardiomyocytes without deleterious effects on cardiac conduction.
Does GS-458967 improve electrophysiological abnormalities in murine and human iPSC-derived cardiomyocyte models of SCN5A overlap syndrome?
Selective inhibition of late sodium current with GS-458967 shows anti-arrhythmic potential in preclinical models of SCN5A overlap syndrome without deleterious effects on cardiac conduction.
AIMS: Selective inhibition of cardiac late sodium current (INaL) is an emerging target in the treatment of ventricular arrhythmias. We investigated the electrophysiological effects of GS-458967 (GS967), a potent, selective inhibitor of INaL, in an overlap syndrome model of both gain and loss of sodium channel function, comprising cardiomyocytes derived from both human SCN5A-1795insD+/- induced pluripotent stem cells (hiPSC-CMs) and mice carrying the homologous mutation Scn5a-1798insD+/-. METHODS AND RESULTS: On patch-clamp analysis, GS967 (300 nmol/l) reduced INaL and action potential (AP) duration in isolated ventricular myocytes from wild type and Scn5a-1798insD+/- mice, as well as in SCN5A-1795insD+/- hiPSC-CMs. GS967 did not affect the amplitude of peak INa, but slowed its recovery, and caused a negative shift in voltage-dependence of INa inactivation. GS967 reduced AP upstroke velocity in Scn5a-1798insD+/- myocytes and SCN5A-1795insD+/- hiPSC-CMs. However, the same concentration of GS967 did not affect conduction velocity in Scn5a-1798insD+/- mouse isolated hearts, as assessed by epicardial mapping. GS967 decreased the amplitude of delayed after depolarizations and prevented triggered activity in mouse Scn5a-1798insD+/- cardiomyocytes. CONCLUSION: The INaL inhibitor GS967 decreases repolarization abnormalities and has anti-arrhythmic effects in the absence of deleterious effects on cardiac conduction. Thus, selective inhibition of INaL constitutes a promising pharmacological treatment of cardiac channelopathies associated with enhanced INaL. Our findings furthermore implement hiPSC-CMs as a valuable tool for assessment of novel pharmacological approaches in inherited sodium channelopathies.
Portero et al. (Fri,) conducted a other in Cardiac channelopathies (overlap syndrome of gain and loss of sodium channel function). GS-458967 (GS967) was evaluated on Electrophysiological effects including late sodium current (INaL) and action potential duration. The INaL inhibitor GS967 decreased repolarization abnormalities and prevented triggered activity in murine and human iPSC-derived cardiomyocytes without deleterious effects on cardiac conduction.
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