Cardiovascular Journal of Africa: Vol 30 No 3 (May/June 2019)

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.

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

) activation, delayed-rectifier K

currents and, last

but not least, Na

-ATPase current (INaK). In association,

AP duration and resting membrane potential are influenced by

acetylcholine-activated K-rectifying currents.

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.

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.

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.

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.

However there were

no genomic changes in atrial INa.

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.

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.

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.

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.

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.

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

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.

During AF, elevated heart rate causes

an increase in intracellular calcium accumulation, engaging

homeostatic defence mechanisms against chronic Ca

overload.

Ical reduction decreases the Ca

inward current, maintaining the

AP plate, shortening AP duration and thus promoting re-entry.

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

channel blockers.

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.

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.

Augmented

JNK activation in aged atria downregulates Cx43 to impair

cell–cell communication and enhance atrial arrhythmogenicity.

There is no evidence of a relationship between AM

administration and Cx43 levels in atrial myocytes. However, no

uncoupling activity of Cx43 was observed

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.

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