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

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 3, May/June 2019

176

AFRICA

post-ganglionic fibres form upper, middle and lower cardiac

nerves, which are responsible for the excitoconductor system and

the contractile fibre innervation. Right sympathetic fibres are

distributed mainly to the excitoconductor system with a more

pronounced impact on heart rate, while left fibres predominantly

are distributed to the contractile myocardium, playing an

important role in contractility by amplifying its activity.

There is a permanent discharge of impulses by releasing

epinephrine, acting on beta-1 receptors. Norepinephrine

stimulates all myocardial properties and mobilises glycogen

and macro-energetic phosphates, and increases membrane

permeability for sodium and calcium, resulting in depolarisation.

Therefore intracellular growth due to beta-adrenergic signals

and spontaneous calcium release from the sarcoplasmic

reticulum may have a pro-arrhythmic effect.

Increased regional

innervation with an increased adrenergic nervous density was the

first type of nervous remodelling associated with arrhythmias.

AM also exerts an anti-adrenergic effect by inhibiting

non-competitive

and

receptors. This is an important aspect

in the use of the intravenous formula, the initial effect being

more prominent in terms of beta-blockade than the effect on

potassium channels.

The mechanism of action differs from

beta-blockers, as it does not effectively block these receptors but

induces downregulation and reduces the binding capacity of beta-

receptors with the regulatory unit: G-adenylate cyclase protein.

Therefore AM can be attributed to class II anti-arrhythmic

drug properties: decreased sinus and NAV automatism as well

as conduction speed (negative chronotropism and dromotropic

effect).

The complex electrophysiological action of this drug is also

accompanied by the anti-arrhythmic effect via other mechanisms,

incompletely elucidated, such as the interference with the action

of thyroid hormones (inhibition of their action at the cardiac

level) in the modulation of the effects of the autonomic nervous

system.

Structural atrial remodelling in AF

Rapid and irregular atrial activation leads to severe systolic

dysfunction of the atrium, completely reversible only in the case

of short periods of AF. For paroxysmal AF, complete atrial

functional recovery occurs after two to three days, while for

persistent AF, the effective atrial refractory period normalises

over days, and atrial activation returns to baseline within a few

weeks. As for contractile function, its normalisation can last for

weeks or even months.

In AF, left atrial (LA) dilation is generally

present, being related to both the severity and underlying disease

leading to the onset of arrhythmia.

LA dilation was highlighted

as a precursor of AF in the Framingham Heart Study and the

Cardiovascular Health Study.

In the case of conversion to sinus rhythm, by either

pharmacological or electrical cardioversion, or through

radiofrequency ablation, LA size may be a prognostic marker

for its recurrence. Dilated LA is a risk factor for the recurrence of

AF post-ablation, being associated with significant remodelling

and it consequently limits the efficacy of ablation.

Atrial

remodelling, especially interstitial fibrosis, is an important factor

in the AF substrate.

The mechanism is not fully known and the

signalling molecules that lead to structural changes may vary

from one patient to another.

There are multiple pro-fibrotic factors in AF (angiotensin II,

TGF-

1, platelet-derived growth factor, endothelin 1, etc.) that

can act independently or synergistically, therefore enhancing

the fibrotic process.

Although the administration of AM is

incriminated for the generation of a pro-fibrotic effect in the

pulmonary parenchyma,

there are no studies confirming such

an effect in the atrial myocardium. Chronic administration of

AM does not influence ventricular remodelling after myocardial

infarction. It does not alter myocardial dimensions, vascular

density or interstitial fibrosis, with no changes in the structure or

function of the left ventricle.

Nearly all AF patients undergoing pharmacological

cardioversion with AM show a recovery of the bilateral atrial

mechanical function in approximately 24 hours, reaching normal

function within seven days post-conversion.

Compared to

propafenone, in AM-treated patients, LA fractional shortening

and total atrial fraction were significantly higher and showed

lower LA stunning.

Inflammation in AF

Several inflammatory markers are associated with AF. Whether

we are talking about an increase in fibrinogen expression, tissue

factor production by monocytes, destruction or endothelial

activation, or interleukin synthesis, these are all mechanisms

where inflammation is associated with pro-thrombotic status,

modifying the impact, clinical presentation and prognosis in AF.

The association between C-reactive protein (CRP) and

AF has long been debated, the direct relationship still being

controversial. In the Copenhagen City Heart Study, the

authors highlighted that elevated plasma CRPs were robustly

associated with increased risk of AF; however, genetically

elevated CRP levels were not. This leads to the conclusion that

elevated plasma CRP per se does not increase the risk for AF.

However, the intracytoplasmic presence of CRP was found in

the atrial cardiomyocytes from patients with paroxysmal AF, in

a significantly higher percentage compared to the control group.

Therefore it can be concluded that local inflammation assessed

by atrial tissue localisation of CRP is more likely to be involved

in paroxysmal rather than persistent AF.

Following conversion to sinus rhythm, CRP levels are

independent predictors of AF recurrence in patients with

persistent or paroxysmal AF, which can be helpful for prediction

of the recurrence of AF. A positive high-sensitivity CRP test

result at baseline can predict a 73% chance of AF recurrence in

the six to 12 months following cardioversion.

Interleukin-2 (IL-2) serum levels in new-onset AF have been

related to pharmaceutical cardioversion outcomes. Elevated

levels of this pro-inflammatory non-vascular cytokine were an

independent predictor for the recurrence of AF after catheter

ablation.

In a similar manner, patients who developed AF

immediately (within 24 hours) after coronary artery bypass

grafting (CABG) had significantly higher IL-2 levels compared

to patients without paroxysmal AF.

TNF-

(tumour necrosis factor alpha) increases IL-6 and

IL-1 levels, inducing a decrease in cardiac contractile proteins

such as

-myosin heavy chain and cardiac

-actin, both of which

have a detrimental role in atrial and ventricular cardiomyocyte

function. In an animal experimental trial, a single dose of

TNF-

was sufficient to induce persistent AF without any