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  •    Genetic Advances in Atrial fibrillation Baby Steps in Unveiling a Complex Disease Process
    Darbhamulla Venkata Nagarajan MBBS, MRCP, Trent Cardiac Centre, Nottingham City Hospital, Nottingham, UK.

    Atrial fibrillation has traditionally been classified as being secondary to underlying structural heart disease or lone AF. This classification, however has now become obsolete with increasing understanding of diverse mechanisms governing lone AF. Much of this is provided by recent genetic advances in AF. Robert et al in their recently published article in JACC (Jason D. Roberts, MD, Michael H. Gollob, MD. Impact of Genetic Discoveries on the Classification of Lone Atrial Fibrillation. J Am Coll Cardiol 2010;55:705–12 ), enumerate the impact of genetic advances in understanding lone AF and propose a classification of lone AF in to mechanistic sub groups.

    Evidence of heritability in AF has been well known for decades. Gene (encoding potassium channel namely KCNQ1) responsible for autosomal dominant form of AF was first identified in year 2003. Since several other genes encoding ion channels have been linked to pathogenesis of lone AF. A gene encoding circulating harmone ANP (atrial natriuretic peptide) has also been implicated. Robert et al, sub-classify lone AF in to six categories based on possible underlying mechanism of AF initiation.

    Enhanced atrial action potential:

    The first causative gene for AF, KCNQ1, was identified through a linkage analysis study of a Chinese family with an autosomal dominant form of lone AF. KCNQ1encodes the pore forming -subunit of the Kv7.1 voltage-gated potassium channel that is responsible for the slow component of the delayed rectifier potassium current (contributes to repolarization of cardiac myocytes). Family members with AF

    were found to carry a mutation affecting amino acid position 140 that resulted in the substitution of a glycine for a serine residue (Ser140Gly). In vitro functional analysis revealed markedly increased current densities conducted by the mutant channel indicating that, unlike the KCNQ1 loss-of-function mutations observed in LQTS type 1, Ser140Gly substitution resulted in a gain of function. The predicted physiological consequences of gain-of function mutations within potassium channels include an

    acceleration of cardiomyocyte repolarization. This enhanced repolarization results in a shortening of the overall action potential duration (APD) and presumably a related reduction in the effective refractory period (ERP). This reduced ERP is likely responsible for the increased predisposition for AF in these affected families, a concept that is consistent with the multiple wavelet hypothesis. After

    the identification of KCNQ1as a causative gene for AF, multiple other gain-of-function mutations within potassium channel genes have been reported to be associated with AF and normal QT intervals (including KCNE2, KCNJ2, and KCNE5).

    Delayed atrial action potential repolarisation:

    Loss of function mutation of the KCNA5gene (encodes the Kv1.5 voltage-gated potassium channel responsible for the ultra rapid component of the delayed rectifier potassium current) was identified in a family with hereditary lone AF. Another ion channel with a known role in mediating action potential duration is the voltage-gated sodium channel Nav1.5. Encoded by the SCN5Agene, Nav1.5 is known to be associated with other disorders that carry an increased risk of AF, including Brugada syndrome, LQTS type 3, and sick sinus syndrome.

    Conduction velocity heterogeneity:

    Mutation of connexin 40 with loss of function was identified in some sporadic cases of lone AF. Connexins are transmembrane spanning proteins that form gap junctions, which serve as intercellular pores, providing low-resistance pathways for the passage of current between adjacent cells. The loss of function associated with these connexin

    mutations, likely results in a predisposition to AF and maintenance of the arrhythmia through mechanisms consistent with an enhanced vulnerability to electrical reentry and an exaggerated dispersion of conduction velocity.

    Cellular hyperexcitability:

    2 studies identified SCN5Again-of-function mutations in patients with lone AF and who did not have LQTS type 3. The mechanism translating cellular hyperexcitability secondary to SCN5Again-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.

    Hormonal modulation of atrial electrophysiology:

     NPPArepresents the most recent gene identified as being causative for AF and, encodes the circulating hormone ANP. ANP is a known mediator of inflammation, and it is likely that 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.

    Cholinergic AF:

    Sympathetic and parasympathetic influences have long been recognized as mediators of the triggers and substrate modification necessary for the development of AF. The greatest density of vagal innervation within the atria occurs at the pulmonary veins, which correspond to the location of rapidly firing ectopic foci capable of driving the arrhythmia. Providing a clue that genetic mutations in the molecular constituents mediating the cardiac vagal response may represent an important, and potentially common, cause of the arrhythmia.

    Genetic studies have revealed heterogenous pathophysiology of lone AF. Genome-wide association studies have provided insight into common genetic loci that carry an increased risk of AF. Identifying common variations within the genome, which, either alone or in combination, may affect the biophysical properties of atrial tissue, remains a priority in future research.


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