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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 3, May/June 2019
AFRICA
177
significant change in cardiac size or overall cardiac function.
The proposed pathophysiological mechanisms include
the increase in serum transforming growth factor beta levels,
which supports the overexpression of MMP-2 (matrix
metalloproteinases) and decreases the expression of Cx40,
decapentaplegic homolog 3 (SMAD-3) and phospho-SMAD3
growth, activating fibroblasts and myofibroblasts, and finally
generating fibrosis and inducing arrhythmogenic substrates.
45
Serum TNF-
α
levels and mRNA expression of TNF-
α
were increased in the left atria of patients with AF; higher in
permanent AF compared to paroxysmal AF, and associated with
LA diameter.
46
However, TNF-
α
levels did not prove useful in
predicting the risk of developing AF or AF recurrence. Although
treatment with infliximab, a TNF-
α
inhibitor, may improve
pre-existing LA abnormalities in patients with rheumatoid
arthritis,
47
there is no evidence of protection against AF. On
the contrary, infusion of this product is associated with the
occurrence of ventricular or supraventricular rhythm disorders.
48
Concerning AM, experimental studies, most of them
performed on animal models or on
in vitro
cell cultures,
have revealed new valences of this drug regarding its anti-
inflammatory effect. The administration of AM has been
shown to ameliorate glutathione depression by increasing the
activity of some catalases, glutathione s-transferase enzymes and
enhancing myeloperoxidase activity; all these anti-inflammatory
mechanisms can lead to an anti-oxidative effect. AM reduces
the activation and mobilisation of neutrophils. It may limit the
activation of human T cells by inhibiting (in a dose-dependent
manner) the production of cytokines, including IL-4, IL-2,
TNF-
α
and interferon-gamma.
49
Impairment of left ventricular function, irrespective of
aetiology, is commonly associated with the onset of AF. AM
is one of the few anti-arrhythmic drugs that can be used with
beneficial results for an ejection fraction of less than 40%. In
an animal model, treatment with AM can decrease plasma
Il-6 levels in viral myocarditis,
50
and it is even able to prevent
remodelling of the left ventricle, improving cardiac function in
some cases of dilative cardiomyopathy.
51
Although serum concentrations of AM and its metabolites
are not routinely used in medical practice, the anti-inflammatory
effects of AM appear to be dose dependent. In patients with
dilative cardiomyopathy, lower serum AM levels (1–10
μ
mol/l)
inhibited the production of TNF-
α
by human monocytes,
molecules with a detrimental role in both heart failure and
AF.
52
On the other hand, high serum AM levels (10–25
μ
mol/l)
stimulated IL-6 production in cultured human thyrocytes, while
1-
μ
mol/l concentrations significantly decreased the levels of this
cytokine.
53
The production of monocyte cytokines and chemokines
stimulated by CRP is also influenced by AM in a dose-
dependent manner. At low concentrations (1–10
μ
mol/l), it has
a beneficial effect, whereas higher levels (25–50
μ
mol/l) stimulate
the synthesis of these pro-inflammatory molecules, most likely
by the cytotoxic effect of AM on monocytes.
51
Different AMdoses may give rise to different results, requiring
a more accurate outline of therapeutic serum levels to avoid its
numerous adverse effects and to achieve a maximum anti-
arrhythmic effect. However, its highly particular metabolism is
well known, with unpredictable desethylamiodarone levels, the
main AM metabolite, with specific pharmacological properties.
This makes it difficult to create a mathematical model for the
prediction of beneficial effects and adverse reactions.
Stress activation in AF
AF may be detected in the setting of an acute stressor, such
as surgery, medical illness or even heavy alcohol consumption
(‘holiday heart syndrome’). It remains unclear whether AF
detected in these circumstances is secondary to a reversible
trigger or it is simply paroxysmal AF.
In human AF, endoplasmic reticulum (ER) stress can be
associated with autophagy and cardiomyocyte remodelling.
Patients with persistent AF showed an accumulation of
autophagosomes and autolysosomes and the presence of
myolysis, which is absent in patients in sinus rhythm. The
attenuation of ER stress results in the conservation of contractile
protein expression, relieving autophagy and protecting from
cardiac remodelling.
54
JNK is a well-characterised stress-response kinase that is
activated in response to various cellular stresses such as ischaemia,
inflammatory cytokines and aging. The activation of JNK2,
a major isoform in the heart, causes abnormal intracellular
Ca
2+
waves and diastolic sarcoplasmic reticulum (SR) Ca
2+
leak, triggering a pro-arrhythmic effect. Recently, it has been
demonstrated that JKN2 activation upregulates the expression
in the aged atrium of CaMKII delta. The latter is a well-known
cardiac pro-arrhythmic molecule that phosphorylates Ca
2+
-
handling proteins, including phospholamban, Ca
2+
-releasing
ryanodine receptors, inositol 1,4,5-trisphosphate receptors and
L-type Ca
2+
channels, thereby playing a crucial role in the
excitation–contraction coupling in the normal heart and enhanced
arrhythmogenicity in pathological cardiac remodelling. JNK2-
driven CaMKII activation can be described as a novel mode of
kinase cross-talk and a causal factor in AF remodelling.
55,56
Heavy episodic drinking is a well-known independent risk
factor for cardiac arrhythmias, most frequently for AF. Alcohol
activates stress-response kinase JNK, which leads to SR Ca
2+
mishandling with changes in cardiac contractile function,
enhancing atrial arrhythmogenicity.
57
Treatment with AM inhibited the JNK signalling pathway
and reduced the activation of JNK on human T cells.
58
Despite
the fact that the activation of T cells plays an important role
in the pathogenesis of AF, there is a need for studies on atrial
myocytes, as the modulation of JNK and CaMKII activity may
contribute to the success of AM in maintenance of sinus rhythm.
The use of AM in patients with AF
AF is a global epidemic, with significant and progressive effects
on estimated disability and mortality. Because ablation therapy
is not accessible worldwide, mainly due to high costs of peri-
procedural complications, anti-arrhythmic therapy remains the
cornerstone in rhythm-control strategy. AM, with its multiple
extra-cardiac adverse effects, is the most efficient anti-arrhythmic
drug. Oral pre-treatment with AM for one month before
cardioversion improved the reversion rate: 88 versus 56–65%
without pre-treatment in patients with persistent AF.
59
AM has
emerged as the most effective agent to prevent the relapse of
AF after electrical cardioversion, with up to 69% of patients
remaining in sinus rhythm after one year; however as many as