![Show Menu](styles/mobile-menu.png)
![Page Background](./../common/page-substrates/page0047.png)
CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 3, May/June 2019
AFRICA
175
10% of cases, other veins such as Marshall’s vein, the inferior vena
cava, upper vena cava, or even left atrial tissue may be the sources
of AF. Exceptionally, the right atrium can be linked to AF.
Electrical remodelling is the first stage in the onset of
arrhythmias. Changes in membrane potentials and in the
physiology of ion channel activation lead to changes in atrial
frequency. Metabolic processes induced by inflammation and
reactive oxygen species cause changes in intracellular ion
concentration, ion channel activity and phosphorylation. In
terms of long-term alteration, we can talk about electrical
remodelling of atrial tissue.
The process substratum is not yet fully elucidated, but certainly
includes impairment of depolarisation and repolarisation. It has
been shown that in AF, alternations in action potential duration
(APD), measured by atrial pacing, occurred at lower cardiac
frequencies of 100–120 beats/min, not being related to restitution
of action potential duration. Spontaneous initiation of AF by
ectopic beats was observed under these conditions. Paroxysmal
oscillations of action potential (AP) are amplified prior to AF,
while in healthy subjects AP alternans only occurs at very high
frequencies at a cycle length of
<
250 ms.
5
Depolarisation involves complex electrophysiological
changes in voltage-dependent Na (INa) current, L-type (ICal)
calcium channels, and cardiac sodium–calcium exchanger
type-1 (NCX1). Repolarisation requires transient-outward K
+
current (I
to
) activation, delayed-rectifier K
+
currents and, last
but not least, Na
+
/K
+
-ATPase current (INaK). In association,
AP duration and resting membrane potential are influenced by
acetylcholine-activated K-rectifying currents.
6
In cardiac myocytes, AM is capable of reducing cell inward-
rectifier potassium current [I(K1)] and single I(K1) channel
activity as a result of a direct blocking action caused by an
interaction with a hydrophobic site within the membrane,
inhibiting single I(K1) channel activity by prolonging the inter-
burst interval.
7
Two-pore-domain potassium (K2P) channels play an
important role in the modulation of cellular excitability.
They mediate background potassium currents, stabilising
resting membrane potential and expediting action potential
repolarisation. In patients with AF, the downregulation of atrial
and ventricular K2P mRNA and protein levels was observed.
8
AM is an inhibitor of cardiac K2P channels, which may
induce prolongation of cardiac repolarisation and AP duration
in patients with high individual plasma concentrations, possibly
contributing to the anti-arrhythmic efficacy of the class III drug.
9
Studies in animal models have shown reduced (INa) as a result
of atrial tachycardia remodelling. These changes contribute to
the slow atrial conduction observed in AF.
10
However there were
no genomic changes in atrial INa.
11
In AF, sodium channel density is approximately 16% lower
than sinus rhythm, accompanied by a 26% decrease in Nav1.5,
an integral membrane protein and tetrodotoxin-resistant voltage-
gated sodium channel subunit. Conversely, there was a 26%
increase in the INa strain in the atria of AF patients.
12
AM preferentially inhibits the Na channels of the atrial
myocardium to the detriment of the ventricle, this selectivity
allowing the control of AF without affecting ventricular
contractility.
13
Because of this property, it remains the only
solution for the rhythm-control strategy in AF with major
depression in chronic heart failure or severe aortic stenosis.
14
As it can determine the decrease in AP V
max
and the
conduction in the myocardial tissue whose excitability depends
on the activation of fast-acting sodium channels, AM has an
electrophysiological profile similar to lidocaine.
15
In patients at risk for AF (e.g. heart failure, mitral stenosis),
atrial myocyte Ical levels were lower compared to low-risk AF
patients, this being secondary to the downregulation process.
16
Atrial remodelling of this arrhythmia causes instability of calcium
homeostasis and contributes to the pro-arrhythmic phenomenon
based on several cellular mechanisms: changes in Ca
2+
capture
by ryanodine receptor (RyR2) gene defects, enhanced RyR2
phosphorylation, increased calcium–calmodulin-dependent
protein kinase II (CaMKII) activity, intracellular calcium
alternans, and by slowing electrical conduction and atrial
interstitial fibrosis encountered in patients with heart failure
and left atrial dilation.
17
During AF, elevated heart rate causes
an increase in intracellular calcium accumulation, engaging
homeostatic defence mechanisms against chronic Ca
2+
overload.
Ical reduction decreases the Ca
2+
inward current, maintaining the
AP plate, shortening AP duration and thus promoting re-entry.
18
AM, but not its active metabolite desethylamiodarone, is
a potent competitive verapamil-like inhibitor, blocking the
calcium influx at Ca-dependent voltage channels. Some authors
suggest that the acute effect of sino-atrial and atrioventricular
node inhibition, vasodilation and negative inotropism may be
attributable to the action of Ca
2+
channel blockers.
19
In the myocardium, the connection through gap junctions
is essential for controlling the electrical impulse. The structural
remodelling of the myocardium is accompanied by gap junction
remodelling with changes in signalling molecules. Changes
in the topology of connexin (Cx) channels are attributed to
electrical remodelling and contribute to impaired conduction
and arrhythmogenic substrate generation. The most abundant
gap junction protein in atrial myocytes is Cx43 and AF is
associated with a low expression of this protein. Cx43 reduces
susceptibility to AF and the downregulation of this Cx mediates
the induction and maintenance of sympathetic AF.
20
Previous studies have shown the importance of c-Jun
N-terminal kinase (JNK), an enzyme from the mitogen-activated
protein kinase family, which binds and phosphorylates c-Jun, a
cellular transcription factor. JNK activation contributes to Cx43
reduction that promotes the development of AF.
21
Augmented
JNK activation in aged atria downregulates Cx43 to impair
cell–cell communication and enhance atrial arrhythmogenicity.
22
There is no evidence of a relationship between AM
administration and Cx43 levels in atrial myocytes. However, no
uncoupling activity of Cx43 was observed
23
after AM therapy,
and moreover, in the case of severe myocardial damage such as
Trypanosoma cruzi
infection, AMproved capable of fully restoring
Cx43 distribution. Treated cultures displayed gap junction plaques
comparable to those of uninfected controls, promoting cardiac
cell recovery with gap junction and cytoskeleton reassembly.
24
Autonomic nervous system remodelling in AF
Autonomous cardiac innervation is extremely complex and plays
an important role in triggering and maintaining AF. Sympathetic
pathways start from the intermediolateral cords of the first
five to six medullary thoracic segments. The post-ganglionic
synapse is located in the cervical and dorsal nodes, from where