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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 2, March/April 2019
84
AFRICA
I
Na,Late
may be a cause of after-depolarisations, spontaneous
diastolic depolarisation, and triggered arrhythmias in atrial
myocytes. In addition, I
Na,Late
increases repolarisation dispersion and
may lead to APD alternans and re-entrant arrhythmias. Several
kinds of I
Na,Late
inhibitors have shown promising clinical effects.
25,26
Ranolazine, a I
Na,Late
blocker, demonstrated anti-AF effectiveness
in persistent AF patients.
27
Other drugs may preferentially inhibit
I
Na,Late
, including anti-arrhythmic drugs in class I (mexiletine,
lidocaine and flecainide) and class III (amiodarone).
28
Our findings reveal selective inhibition of All on I
Na,Late
of
atrial myocytes from SHR in a concentration-dependent manner.
In previous studies, we found that All could reduce delayed after-
depolarisations and trigger activities in mice cardiomyocytes
induced by isoproterenol.
9,29
This discovery provides evidence for
the inhibition of atrial ectopic rhythm and a reduction in AF.
All may rescue trafficking deficiencies and restore the
cellular electrophysiological characteristics of SCN5A-T353I,
causing Brugada syndrome and LQT3.
10
We also found that All
decreased transmural repolarising ionic ingredients of outward
potassium current (I
to
) and slowly delayed the rectifier potassium
current (I
Ks
).
8
These findings provide a novel perspective on the
application of All in atrial anti-arrhythmogenesis in clinical
settings.
Limitations
Electrical remodelling of atrial myocytes is found in age and chronic
disease conditions. More recently, Yan
et al
.
30
reported that the
stress-response kinase JNK isoform 2 (JNK2) plays an important
role in promoting atrial arrhythmias. JNK is activated in response
to various cellular stresses such as aging, ischaemia, inflammation,
cardiac hypertrophy and alcohol use.
31-33
Their results showed that
JNK2 activation caused abnormal intracellular calcium waves and
diastolic sarcoplasmic reticulum Ca
2+
leak in the atrial myocytes.
30
I
Na,Late
is enhanced in the myocytes of animals with chronic heart
failure and patients with hypertrophic cardiomyopathy. We do
not know how the JNK changed in the SHR atrial myocytes, and
whether it affected the late sodium current. The effect of All on the
JNK signalling pathway requires further research.
I
Na,Late
may increase calcium influx via the reverse mode of the
sodium/calcium exchanger. Intracellular Ca
2+
levels increase and
cause a series of pathophysiological changes, such as structural
and electrical remodelling of the atrium. In this study, we focused
on the effect of All on the I
Na,Late
from SHR atrial myocytes. The
change in Ca
2+
concentration and its molecular regulation of
signalling pathways was not explored. It would be necessary to
investigate the concentration of Ca
2+
and the activity of CaMKII
in SHR atrial cells.
WT FS FS-All
TI
TI-All
EK EK-All
1
Na,L ate
(pA/pF)
6.0
4.8
3.6
2.4
1.2
0.0
**
**
**
##
&&
∆∆
All Log C (
μ
M)
TI-All
EK-All
FS-All
1
10
100
Normal current
1.0
0.8
0.6
0.4
0.2
0.0
Fig. 6.
Effect of All on I
Na,late
of three SCN5A mutations in HEK293 cells. (A) Representative I
Na, late
current traces recorded from WT,
F1473S, T353I and E1784K before and after exposure to 30
μ
M All. (B) At a test potential of –20 mV, I
Na,late
current densities
of F1473S, T353I and E1784K increased significantly compared with WT. After exposure to 30
μ
M All, I
Na,late
current densities
decreased significantly. (C) Inhibition effects of All on I
Na,late
in a concentration-dependent manner. IC
50
was 15.2
±
2.2
μ
M
for F1473S, 41.8
±
3.6
μ
M for T535I, and 18.1
±
3.2
μ
M for E1784K. **
p
<
0.01, compared with WT.
∆∆
p
,
&&
p
and
##
p
<
0.01,
compared with FS, TI and EK, respectively.
A
B
C