Portero, Vincent;
Hoekstra, Maaike;
Verkerk, Arie O;
Mengarelli, Isabella;
Davis, Richard P;
Freund, Christian;
Bezzina, Connie R;
Belardinelli, Luiz;
Rajamani, Sridharan;
Veldkamp, Marieke W;
Remme, Carol Ann
Abstract 14019: Electrophysiological Effects of the Late Sodium Current Inhibitor GS967 in Scn5a -1798insD Mouse and Human SCN5A -1795insD iPSC-derived Cardiomyocytes
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Media type:
E-Article
Title:
Abstract 14019: Electrophysiological Effects of the Late Sodium Current Inhibitor GS967 in Scn5a -1798insD Mouse and Human SCN5A -1795insD iPSC-derived Cardiomyocytes
Contributor:
Portero, Vincent;
Hoekstra, Maaike;
Verkerk, Arie O;
Mengarelli, Isabella;
Davis, Richard P;
Freund, Christian;
Bezzina, Connie R;
Belardinelli, Luiz;
Rajamani, Sridharan;
Veldkamp, Marieke W;
Remme, Carol Ann
Description:
<jats:p>
<jats:bold>Background and Aim:</jats:bold>
Selective inhibition of cardiac late sodium current (I
<jats:sub>Na,L</jats:sub>
)
<jats:sub />
is an emerging target in the treatment of ventricular arrhythmias. The electrophysiological effects of GS967, a potent I
<jats:sub>Na,L</jats:sub>
inhibitor, were investigated in an overlap syndrome model of both gain and loss of sodium channel function, comprising cardiomyocytes derived from human
<jats:italic>SCN5A</jats:italic>
-1795insD induced pluripotent stem cells (iPSC-CMs) and mice carrying the homologous mutation
<jats:italic>Scn5a</jats:italic>
-1798insD.
</jats:p>
<jats:p>
<jats:bold>Methods and Results:</jats:bold>
On patch-clamp analysis, isolated mouse
<jats:italic>Scn5a</jats:italic>
-1798insD cardiomyocytes and human
<jats:italic>SCN5A</jats:italic>
-1795insD iPSC-CMs showed decreased peak I
<jats:sub>Na</jats:sub>
and action potential (AP) upstroke velocity (Vmax) and increased I
<jats:sub>Na,L</jats:sub>
and AP duration at 90% repolarization (APD
<jats:sub>90</jats:sub>
) as compared to wild-type. GS967 (50-300 nM) significantly decreased APD
<jats:sub>90</jats:sub>
in mouse
<jats:italic>Scn5a</jats:italic>
-1798insD cardiomyocytes by 8±2% (mean±SEM) at 50 nM (n=7), 13±3% at 100 nM (n=11) and 20±5% at 300 nM (n=6) (all
<jats:italic>p</jats:italic>
<0.01 vs. control), without affecting Vmax. GS967 (300 nM) selectively inhibited I
<jats:sub>NaL</jats:sub>
in mouse
<jats:italic>Scn5a</jats:italic>
-1798insD cardiomyocytes (GS967-sensitive current of 0.7±0.1 pA/pF, n=6), but had no effect on peak I
<jats:sub>Na</jats:sub>
<jats:italic>.</jats:italic>
Furthermore, GS967 (100 nM) suppressed fast (5 Hz) pacing-induced afterpotentials and triggered activity. In human
<jats:italic>SCN5A</jats:italic>
-1795insD iPSC-CMs (n=6), GS967 (300 nM) significantly reduced APD
<jats:sub>90</jats:sub>
without affecting the resting membrane potential or Vmax. In Langendorff-perfused, isolated mouse
<jats:italic>Scn5a</jats:italic>
-1798insD hearts (n=5), GS967 (300 nM) had no effect on ventricular activation time or conduction velocity (as assessed by epicardial mapping).
</jats:p>
<jats:p>
<jats:bold>Conclusion:</jats:bold>
Selective inhibition of I
<jats:sub>NaL</jats:sub>
by GS967 attenuated AP prolongation and prevented pro-arrhythmic activity in mouse
<jats:italic>Scn5a</jats:italic>
-1798insD cardiomyocytes and human SCN5A-1795insD iPSC-CMs, thus suppressing the gain-of-function features of this overlap syndrome mutation. Importantly, these beneficial actions of GS967 occurred in the absence of deleterious effects on sodium channel availability or cardiac conduction, despite a pre-existing decrease in peak I
<jats:sub>Na</jats:sub>
. Thus, selective inhibition of I
<jats:sub>Na,L</jats:sub>
constitutes a promising pharmacological treatment of cardiac channelopathies associated with enhanced I
<jats:sub>NaL</jats:sub>
, even in overlap syndromes whereby peak I
<jats:sub>Na</jats:sub>
is decreased.
</jats:p>