Anti-arrhythmic potential of the late sodium current inhibitor GS-458967 in murine Scn5a-1798insD(+/-) and human SCN5A-1795insD(+/-) iPSC-derived cardiomyocytes

作者：Portero Vincent; Casini Simona; Hoekstra Maaike; Verkerk Arie O; Mengarelli Isabella; Belardinelli Luiz; Rajamani Sridharan; Wilde Arthur A M; Bezzina Connie R; Veldkamp MariekeW; Remme Carol Ann

来源：Cardiovascular Research, 2017, 113(7): 829-838.

DOI：10.1093/cvr/cvx077

• SCN5A
• Sudden cardiac death
• Late sodium current
• Long QT syndrome type 3
• hiPSC-CMs
• Sodium channels

Aims Selective inhibition of cardiac late sodium current (I-NaL) is an emerging target in the treatment of ventricular arrhythmias. We investigated the electrophysiological effects of GS-458967 (GS967), a potent, selective inhibitor of I-NaL, 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 I-NaL 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 I-Na, but slowed its recovery, and caused a negative shift in voltage-dependence of I-Na 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 I-NaL inhibitor GS967 decreases repolarization abnormalities and has anti-arrhythmic effects in the absence of deleterious effects on cardiac conduction. Thus, selective inhibition of I-NaL constitutes a promising pharmacological treatment of cardiac channelopathies associated with enhanced I-NaL. Our findings furthermore implement hiPSC-CMs as a valuable tool for assessment of novel pharmacological approaches in inherited sodium channelopathies.

• 出版日期2017-6-1