Cardiovascular Journal of Africa: Vol 30 No 2 (March/April 2019)

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 2, March/April 2019 82 AFRICA
potential of –20 mV, the INa,Late densities of the three mutations
increased from 0.81 ± 0.03 pA/pF for the WT to 5.02 ± 0.13 pA/
pF for F1473S, 594 ± 0.47 pA/pF for T535I, and 4.12 ± 0.12 pA/
pF for E1784K, respectively (p < 0.01, n = 10). After exposure to
30 μM All, the INa,Late densities of SCN5A mutations decreased
to 1.08 ± 0.02 pA/pF for F1473S, 1.32 ± 0.50 pA/pF for T535I,
and 0.97 ± 0.31 pA/pF for E1784K, respectively (p < 0.01, n =
10; Fig. 6B).
The effects of different concentrations of All on INa,Late of the
SCN5A mutations were investigated. INa,Late was inhibited by All
in a concentration-dependent manner. IC50 was 15.2 ± 2.2 μM
for F1473S, 41.8 ± 3.6 μM for T535I, and 18.1 ± 3.2 μ M for
E1784K, respectively. The Hill coefficients were 0.87, 1.29 and
0.98, respectively (Fig. 6C).
Discussion
In epidemiological studies, the risk of AF was estimated to
be 1.42 times higher in hypertensive patients compared with
normotensives. Hypertension, age and diabetes are prominent risk
factors for AF.11,12 Normally, the sodium channel was inactivated
within a few milliseconds of depolarisation. Some channels
remained open, creating a small but persistent influx of Na+
throughout the plateau of AP during pathological conditions.13,14
Especially in chronic physiological and pathological processes
(such as in the case of aging, myocardial hypertrophy, sick
sinus syndrome and heart failure), sodium channels may be
remodelling. Chang et al. found down-regulation of Nav1.5
protein expression and reduced INa density in failing hearts
and ischaemia–reperfusion injury. Nav1.5 contributes to
arrhythmogenesis in heart failure due to the generation of INa,Late.15
Up-regulated Nav1.8 augmented I Na,Late in human hypertrophied
myocardium and prolonged the APD.16,17
Sick sinus syndrome is a common arrhythmia often associated
with aging or organic heart diseases. The disease-causing gene
is closely related to the sodium channel. 18 The SHR cells
showed electrophysiological remodelling of the left atrium,
leading to increased vulnerability to burst pacing-induced atrial
arrhythmias.2
Our investigation demonstrated larger INa,Late and longer APD
in SHR atrial cells compared with WKY cells. The magnitude
of INa,Late may increase significantly in chronic pathological
settings. Sossalla et al.19 reported that INa,Late increased in atrial
myocytes isolated from the right atrial appendage of persistent
AF patients. I Na,Late densities in left atria have also been reported
to increase in a rabbit left ventricular hypertrophy model caused
by hypertension. 13
INa,Late contributes to the plateau phase of the cardiac AP and
is related to arrhythmogenesis under pathological conditions.
Although the contribution is small relative to the peak current,
INa,Late cannot be neglected. A small, persistent Na+ current
prolongs the plateau APD and induces a Na+ load that may
indirectly increase intracellular Ca2+ concentrations. Both AP
prolongation and Ca2+ overload are reported to be the main
causes of AF. 20,21 Our findings suggest that enhanced INa,Late is
involved in the occurrence and development of AF.
We also found that the window currents of SHR atrial cells
were enhanced. Several factors contribute to the late sodium
WKY
SHR
All 30 μM WKY SHR All 30 μM
I Na,late
/I
peak
(%)
1.0
0.8
0.6
0.4
0.2
0.0
**
##
WKY SHR All 30 μM
I Na,peak
(pA/pF)
0
–50
–100
–150
–200
–250 Log [C] μM
0.1 1 10 100 1000
Fraction of maximum
1.0
0.8
0.6
0.4
0.2
0.0
Fig. 3. Effect of All on late sodium current (INa,Late ) of SHR myocytes. (A) Representative current traces recorded from WKY and
SHR cells with 30 μ M All. INa,Late of SHR myocytes was significantly larger than that of WKY cells, which was inhibited by
All. (B) Incremental ratio of I Na,Late /INa,peak in SHR cells reduced from 0.71 ± 0.02 to 0.37 ± 0.02% and ended at 0.09 ± 0.01%
of WKY cells. (C) At a test potential of –20 mV, INa,peak did not change in the three groups. (D) INa,Late was inhibited by All in a
concentration-dependent manner. IC50 was 16.8 ± 2.2 μM, Hill coefficient: 0.96 (n = 15). **p < 0.01 vs WKY group. ##p < 0.01
vs SHR group.
A
C
B
D