Page 15 - ADD-ON ABLATION SURGERY IN PATIENTS WITH ATRIAL FIBRILLATION

controlling cardiac excitability such as the potassium channel genes KCNQ1,
KCNE2, KCNJ2 KCNE5, KCNA5 and KCNH2 or the SCN5A sodium channel 1 gene37-42. The final effect of ion channel mutations is reduced action potential
duration. Consequently, carriers of genetic channelopathies have a short atrial
refractory period that creates a vulnerable substrate for the development of AF.
The mechanism-translating cellular hyper- excitability secondary to SCN5A gain-
of-function mutations into the phenotype of AF potentially relates to enhanced
automaticity of atrial cardiomyocytes. The resultant triggers, in the setting of an
ideal substrate such as the pulmonary veins, may be sufficient to both induce and
maintain AF. Subsequent screening of LAF cohorts suggested that these channels
were a rare cause of the arrhythmia43, 44. However, the association between
Brugada’s syndrome and AF supports the pathogenic rule of SCN5A45.
These findings implied that there were likely other classes of genes that played
an important role in the development of the more common sporadic form of
AF. Attractive candidate genes included connexins, trans-membrane-spanning
proteins that form gap junctions, which serve as intercellular pores, providing low-resistance pathways for the passage of current between adjacent cells46. Of
the 5-connexin isoforms expressed in the heart, connexin 40 (Cx40) seemed the
most intriguing in the context of AF given its high level of expression within the
atria and absence from ventricular myocardium47. Defects in Cx40 are expected
to lead to increased propensity to AF through an impaired electrical coupling
between cells and decreased atrial conduction velocity. Another study48 has
highlighted the role of age-related accumulation of mitochondrial DNA mutations.
The most recent culprit gene identified (NPPA) encodes a circulating hormone,
the atrial natriuretic peptide (ANP) 49. Before this work, ANP had generally been
viewed as a cardio protective hormone with an important role in sodium balance
and blood pressure regulation50. There was evidence, however, that ANP was
capable of modulating the activity of various ion channels within the heart51, 52.
Although the potential role of ANP in directly modulating atrial electrophysiology
and promoting an AF substrate is intriguing, other pro-arrhythmic actions of ANP
are also conceivable, an example being inflammation that could stem from the
important role of ANP in the regulation of the innate immune system53, 54. Given
that ANP is a known mediator of inflammation, long-term exposure to altered
levels of ANP might induce structural changes related to inflammation that
ultimately result in atrial fibrosis and subsequent development of an AF substrate.
Other peptides that have been investigated are the serum B-natriuretic peptide
Introduction
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