Biomedical Engineering Reference
In-Depth Information
causes slower or incomplete inactivation, or enhanced Na
v
1.4 activation [
58
].
Interestingly, low temperatures could worsen certain types of myotonias, by
disrupting slow channel inactivation, and lead to flaccid paralysis [
59
,
60
]. PPs
are inherited sodium channelopathies, categorized as either hyper- or hypo-kalemic
according to associated circulating potassium concentrations, which induce muscle
weakness and transient inability to move. HyperPP is characterized by a strong
depolarization leading to inactivation of Na
v
1.4 channels and depolarization block,
which cause paralysis. High potassium serum levels are a specific feature of
hyperPP [
61
]. In contrast, hypoPP loss-of-function channel mutations induce
Na
v
1.4 channel inactivation, by stabilizing the inactivated state [
62
].
2.4.5 Cardiovascular Diseases
Na
v
1.5, located in the sarcolemma of atrial and ventricular myocytes and the
Purkinje fibers, is the VGSC subunits responsible for the large inward depolarizing
currents (I
Na
) occurring during phase 0 of the cardiac action potential. By doing so,
I
Na
regulate cardiac excitability and conduction velocity of electrical stimuli
through the heart [
63
]. The importance of VGSC in the normal cardiac electrical
function has been accentuated by the discovery of channelopathies linked with
mutations in
SCN5A
, the gene encoding the cardiac Na
v
1.5 subunits [
64
,
65
]. These
diseases include long QT syndrome type 3 (LQT-3), Brugada syndrome (BrS),
progressive cardiac conduction disease (PCCD), dilated cardiomyopathy (DCM),
sick sinus syndrome (SSS), atrial fibrillation (AFib), sudden infant death syndrome
(SIDS), and overlap syndromes. LQT-3 is a condition where most
SCN5A
mutations typically disrupt fast inactivation of the sodium current, allowing for
sodium channels to reopen, resulting in a persistent (or sustained) inward current
during the action potential plateau phase [
66
]. Consequently, delayed repolarization
and action potential prolongation occurs, and early after-depolarizations may
subsequently trigger torsades de pointes and sudden death. Alternatively, certain
mutated Na
v
1.5 subunits less commonly cause LQT-3 through increased window
current, reduced or destabilized slow inactivation, faster recovery from inactivation
(causing increased sodium channel availability), and/or increased peak sodium
current density. BrS is a familial disorder characterized by ventricular fibrillation
sometime causing sudden cardiac death in otherwise healthy individuals at a
relatively young age. Numerous
SCN5A
mutations displayed by BrS patients
have been identified, most of which produce loss of function, either through
decreased trafficking and membrane surface channel expression, or through altered
channel gating properties. VGSC
b
-subunits are also expressed in the heart, where
-subunits increase the density of Na
+
channels at
the cell membrane, modulate their biophysical properties, and play a role in cell
adhesion and recruitment of anchoring proteins such as ankyrins. Recently, mutated
SCN1B-SCN4B
have been found in sodium channelopathies displaying phenotypic
cardiac disorders [
67
]. Besides being characteristic of mutated channels associated
with genetic channelopathies, cardiac VGSC dysfunctions also occur in acquired
they play multiple roles. Briefly,
b
