Biomedical Engineering Reference
In-Depth Information
pathological states such as myocardial ischemia and heart failure, where they
produce conduction disturbances and ventricular arrhythmias [
65
]. During both
acute and chronic myocardial ischemia, local metabolic changes take place within
the myocardium, which lead to inactivation of sodium currents and to consequent
inhibition of cardiac excitability and electrical conduction. In particular, conduction
slowing is considered a pro-arrhythmic factor [
68
,
69
]. Cardiac electrophysiologi-
cal properties, including changes in ion channels, are altered also in heart failure. In
such condition, VGSC impaired functioning is part of a complex pathological
network and may contribute to arrhythmogenesis by different pathways. For
instance, sodium channel inability to inactivate, arising during heart failure, induces
persistent sodium inward currents during zero phase, which may delay repolariza-
tion, prolong action potential duration, and alter intracellular sodium and calcium
homeostasis, potentially predisposing to arrhythmogenesis [
70
]. In addition to
increased inward current, loss of cardiac VGSCs may occur during heart failure,
generating conduction slowing and ventricular reentrant arrhythmias [
71
].
2.4.6 Neurodegenerative Diseases
VGSCs have been proposed to play a role in processes involving either acute or
progressive neuronal loss, typical of stroke, ischemia and neurodegenerative
diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS),
Parkinson disease (PD), and Huntington disease (HD) [
72
,
73
]. It was hypothesized
that in all those cases, characterized by a decreased energy supply, causing
impaired activity of Na
+
/K
+
-ATP-depending pumps and membrane depolarization,
there may be a greater persistent Na
+
conductance, most likely mediated by Na
v
1.6
subunits. Na
+
overload inside the axon, combined to K
+
efflux, may lead to Ca
2+
accumulation via reversal of the Na
+
/Ca
++
exchanger, thus triggering a pathogenic
cascade, which ends with axonal injury and eventually with neuronal loss. An
increase in the persistent Na
+
conductance, operating at rest in motor axons, is
likely to contribute to the peripheral hyperexcitability in ALS, leading to the typical
symptoms of cramps and fasciculations, and possibly causing abnormal glutamate
release, which may have a major role in neurodegeneration [
74
,
75
]. Moreover,
VGSCs (in particular Na
v
1.5 and Na
v
1.6) are upregulated in activated microglia
and microphages in models of autoimmune and inflammatory disorders, such as
MS, and might be involved in the phagocytic ability or contribute to the migration
of those cells, thus playing a role in the propagation of the inflammatory cascade
[
76
,
77
].
2.4.7 Psychiatric Disorders
VGSC blockers have displayed beneficial effects in the treatment of various
psychiatric disorders such as bipolar depression (BD) and borderline personality
disorder (BPD) [
78
,
79
]. Lately, mutated sodium channels have been found in
