ATRIAL FIBRILLATION (FA)

1. Genetic basis
2. Treatment
3. References
   

Atrial fibrillation (AF) is the most prevalent cardiac rhythm abnormality and is a major cause of morbidity and mortality. Its prevalence increases with age (from <1% at 50-60 years, to 5-15% at 80 years or older) and is associated with increased cardiovascular morbidity and mortality. AF increases risk throughout the cardiovascular continuum, as it is associated with a nearly doubled risk of death and an almost 5-fold increase in the risk of stroke compared to patients in sinus rhythm. Although AF can occur in apparently healthy individuals, more than 70% of patients with AF present structural heart diseases (i.e., hypertension, cardiac hypertrophy, coronary artery disease, heart failure, valvular diseases, myocardiopathies) or non-cardiac diseases (diabetes mellitus, hyperthyroidism, obesity, obstructive sleep apnea and pulmonary diseases) (Kirchhof et al., 2016; January et al., 2014). However, in recent years, population-based studies suggested that the commonly occurring AF phenotype has a significant genetic component. Indeed, At least 5% of all patients with AF and 15% with lone AF had a positive family history. A family history of lone AF is associated with substantial risk of lone AF, with the strongest risks associated with young age at onset, multiple affected relatives, and in first-degree relatives (Darbar et al., 2003, 2008; Ellinor et al., 2005). Indeed, for individuals in whom a first-degree relative is diagnosed with lone AF, the risk of developing AF is significantly higher than that of the general population (Ellinor et al., 2005), suggesting a Mendelian genetic contribution to the etiology of this common trait.

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1. Genetic basis

Linkage analysis and candidate-gene sequencing have identified multiple mutations in monogenic AF families and isolated AF cases. The majority of reported mutations for familial forms of AF are located in genes that encode ion channel subunits. However, while familial AF is caused by single gene mutations, the form of AF encountered in everyday clinical practice is likely to be a more complex trait, which is caused by multiple genetic variants interacting with environmental factors. The Table 1 shows a range of common variants in ion channels and non-ion channel genes associated with AF.

The idiopathic AF has been associated with mutations in genes encoding both the a- and b-subunits of the voltage-gated Na+ (SCN5A, SCN1B and SCNB2) and K+ channels [KCNA5, KCNQ1, KCNE2, KCNJ2, KCNJ8 and KCNH2], producing an inhomogeneous shortening of atrial APD and refrectoriness (Chen et al., 2003; Darbar et al., 2008; Delaney et al., 2012; Mahida et al., 2011; Olson et al., 2006; Xia et al., 2005; Yang et al., 2004). However, because some of these genes are also expressed in the ventricles, it is no surprise that the FA appears in patients with LQTS, SQTC, SRT or SBR.

Mutation scans identified a missense mutation in SCN5A (D1275N) that cosegregated with an age-dependent, variably expressed phenotype of dilated cardiomyopathy (DCM), AF, impaired automaticity, and conduction delay (Olson et al., 2005). Another loss-of-function SCN5A mutation (N1986K) produces a hyperpolarized shift of steady-state inactivation. One family member with the N1986K mutation had associated conduction system disease (Ellinor et al., 2008). Watanabe et al (2009) reported mutations in SCN1B (R85H, D153N) and in SCN2B (R28Q, R28W) genes in patients with AF and a type 1 ECG pattern of the BrS. The coexpression of these mutant b subunits with the WT a subunit reduced the INa and produce a delayed channel activation indicating a loss-of-function effect (Watanabe et al., 2009). Loss-of-function mutations of SCN5A may predispose to AF by slowing intra-atrial conduction velocity and shortening atrial APD and refractoriness and atrial re-entry wavelength (Kneller et al., 2005); additionally, the attenuation of Na+ current also destabilizes high-frequency rotors. Conversely, some gain-of-function  SCN5A mutations (M1875T, K1493R) were associated with familial AF. They produced a pronounced depolarized shift of the voltage dependence of steady-state inactivation and increased atrial excitability, without changes in the QT interval of the affected individuals (Makiyama et al., 2008; Li et al., 2009). Benito et al (2008) described a three-generation family with a mixed phenotype of LQTS3 and paroxysmal AF due to a gain-of-function mutation (Y1795C) in SCN5A and Johnson et al (2008) reported a mixed phenotype of LQT3 and AF, further supporting the role of gain-of-function SCN5A mutations in AF. Sodium channel mutations may cause AF because an increase in inward Na+ current induce triggered activity and stabilize high-frequency rotors (Kneller et al., 2005).

A loss-of-function mutation (E375X, T527M, A576V, E610K) in the KCNA5 gene encoding the Kv1.5 channel which underlies the ultrarapid delayed-rectifier (IKur) current is associated with AF (Olson et al., 2006; Yang et al., 2009). IKur is an important repolarizing current specific to the atrium. The E375X mutant channel fails to generate IKur and exerts a dominant-negative effect; loss of channel function translates into AP prolongation and early after-depolarizations in human atrial myocytes with stress, which would be predicted to promote initiation of AF (Olson et al., 2006).

The missense mutation S140G in KCNQ1 causes an increase in IKs density due to a marked slowing of IKs deactivation (Restier et al., 2008). Some patients with idiopathic AF, atrial dilatation and arterial hypertension present mutations in the KCNQ1 gene that shorten the atrial APD, which confirms the association of AF with channelopathies and structural abnormalities. Some polymorphisms (G38KCNE1 when co-expressed with KCNQ1 and SCN5A H558R) increase IKs and the risk of FA.

Mutations in IKs channel β-subunits (encoded by KCNE1-5 genes) have been described in patients with familial AF. R27C KCNE2 and L65F KCNE5 mutations produce a gain-of-function effect (Yang et al., 2004; Ravn et al., 2008). A gain-of-function mutation in the KCNJ2 gene (V931I) has been described in a Chinese kindred (Xia et al., 2005). This mutation was not associated with changes in the QT interval.

KCNJ8  encodes for the Kir6.1 subunit of the KATP inward rectifying potassiumis expressed in both atria and ventricles. The KCNJ8-S422L mutation is associated with both increased AF susceptibility and ERS indicating a role for Kir 6.1 KATP channel in both ventricular and atrial repolarization (Delaney et al., 2012).

The Table also show a range of common variants in ion channels and non-ion channel genes associated with AF.

(+): gain-of-function. (-): loss-of-function

Genome-wide association study (GWAS) involve genotyping up to a million common variants, or single nucleotide polymorphisms (SNPs), distributed throughout the genome and comparing their frequency between AF and control cohorts.   The common variants identified by GWAS are located either within or in proximity to compelling candidate genes for AF. The results of these studies are summarised in Table 2.

These studies identified a very strong association of familial AF with a single nucleotide polymorphisms (SNPs) at chromosome 4q25 (Gudbjartsson et al., 2007; Käab et al., 2009; Body et al., 2009; Ellinor et al., 2010). Variants in two ion channel genes, KCNN3 and HCN4, have been associated with lone atrial fibrillation (Ellinor et al., 2010, 2012). KCNN3 encodes a calcium-activated potassium channel (SK3 channel), which is abundantly expressed in the atrium and HCN4 , the hyperpolarisation-activated, cyclic nucleotide-gated cation channel 4, which underlies the pacemaker potential. More recently, Ellinor and al (2012) performed a meta-analysis and replication using over 12,000 cases and identified a total of 9 risk loci. SNPs at the 4q25 locus conferred a relative risk of 1.64 (p = 1.8 × 10–74), while values at other loci were 1.13 to 1.24. The original 4q25 SNPs are located about 150,000 base pairs away from PITX2 (Paired Like Homeodomain 2). PITX2 is a cardiac homeobox transcription factor that mediates asymetrical development of the heart and inhibits left-sided pacemaker specification (Logan et al., 1998). Deletion of Pitx2c (a cardiac-specific isoform implicated in early left-right differentiation in the heart) in mice resulted in failure of formation of the pulmonary vein myocardial sleeve, the site of origin of the abnormal automaticity that commonly drives AF (Mommersteeg et al., 2007). Moreover, Pitx2 allele deletion increased susceptibility to AF while Pitx2 prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification (Wang et al., 2010). These data strongly suggested that SNPs at the 4q25 locus confer AF risk by modulating PITZ function. Very recently, Lubitz et al. (2014) confirmed that the 4q25 locus acts by modulating PITX2 function and that combinations of independent SNPs at the 4q25 locus contribute in an additive fashion to AF risk. The paired-related homeobox gene PRRX1 has been implicated as a mediator of development of the pulmonary veins (Ihida-Stansbury et al., 2004). Other potentially interesting genes at GWAS loci include: SYNPO2L and MYOZ1 that encode signalling proteins that localise to the Z-disc and modulate cardiac sarcomeric function (Frey et al., 2002; Beqqali et al., 2010), CAV1 encodes the scaffolding protein caveolin 1 that interact with ion channels, including HCN4 and KCNN3 (Vaidyanathan et al., 2013; Barbuti et al., 2012).

The identification of genetic variants that contribute to AF susceptibility could be of value for determining risk of future AF in asymptomatic individuals, uncover novel molecular targets for pharmacotherapy and potentially be of use in predicting response to therapy in AF patients.

Other mutations are located in genes that do not encode ion channels such as:

1) the NUP155 gene encoding the nuclear pore complex protein Nup155 regulating the interchange of macromolecules between the nucleus and cytoplasm (Zhang et al., 2008). It has been proposed that NUP155 deficiency may influence Ca²⁺ handling proteins and ion channels shortening the atrial APD or induce myocyte apoptosis and cardiac fibrosis which may create a substrate for reentry.
2) GJA5 gene encodes the high conductance connexin 40 (Cx40) which contributes to the electrical synchronization of the atrium and the rapid conduction of impulses in the His-Purkinje (Gollob et al., 2006; Sun et al., 2013). In the human heart, cardiac Cx40 remodelling may lead to abnormal electrical coupling, forming an electrophysiological matrix with potential arrhythmogenic effect (Sever et al., 2004).  By reducing Cx40 protein levels, two closely linked polymorphisms in the promoter region of the connexin40 gene (GJA5) were associated with enhanced atrial vulnerability and increased risk for idiopathic AF (Groenewegen et al., 2003; Firouzi  et al., 2004). Additionally, the loss-of-function mutations of Cx40 were identified in patients with sporadic AF (Gollob et al., 2006). 
3) NPPA gene encoding a mutant atrial natriuretic peptide (ANP). A heterozygous frameshift mutation in NPPA has been identified in an AF family spanning three generations; the affected members exhibited a transition from paroxysmal to chronic AF accompanied by atrial arrest in their forties (Hodgson-Zingman  et al., 2008). The mutation markedly increases the levels of mutant ANP, which increases cGMP signaling leading to a shortening of atrial APD and refrectoriness, thus providing an arrhythmia substrate (Crozier et al., 1993). An altenative explanation is that excessive ANP may cause structural atrial remodelling due to its pro-apoptotic effect. Another mutation, R150Q, described in six AF families and is characterized by progressive, extreme biatrial dilatation and atrial standstill (Disertori et al., 2013). As already mentioned, ANP shortens both atrial conduction times and the effective refractory period, thus providing an arrhythmia substrate (Crozier et al., 1993).

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2. Treatment

It is described in the current Guidelines for the management of patients with atrial fibrillation (Kirchhof et al., 2016; January et al., 2014).

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3. References

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