Do genetics help to better understand the underlying mechanisms of atrial fibrillation?

Atrial fibrillation (AF) commonly occurs in the context of structural heart disease and is accompanied by atrial remodelling. The latter refers to any change in atrial function that promotes AF or occurs as a consequence of the arrhythmia. Atrial remodelling in the aged heart and during heart failure is characterized by pronounced fibrosis leading to heterogeneous slowing conduction of and prolongation of effective refractory period (ERP). In contrast, atrial remodelling induced by tachycardia is associated with shorter ERP and impaired rate adaptation. Nevertheless, atrial remodelling cannot be an absolute prerequisite for AF because the arrhythmia may also occur in structurally normal hearts, alluding to the existence of acquired or genetically determined predisposing factors. Current knowledge of the molecular identity of the predisposing factors is, however, limited. Fatini et al. provide evidence that susceptibility to nonvalvular AF (NVAF) may be enhanced in association with certain single nucleotide polymorphisms in the genes encoding the accessory Kþ channel subunit minK and the endothelial nitric oxide synthase (eNOS). They studied a serine to glycine exchange in position 38 of minK protein (minK S38G) and several polymorphisms in the eNOS gene including G894T nucleotide exchange in exon 7, a T/C exchange in the promoter region (2T786C), and the eNOS 4a/4b polymorphism. In more than 300 consecutive patients with NVAF, distribution of allele frequencies for minK S38G and eNOS2T786C, but not for eNOS G894T and 4a/4b polymorphisms, was significantly different when compared with healthy volunteers. However, only the minK 38G allele was significantly associated with enhanced susceptibility to NVAF. Interestingly, the contemporary presence of minK 38G and eNOS 2786C alleles resulted in stronger predisposition for NVAF than the minK gene variant alone. Do these findings contribute to a better understanding of the mechanisms for AF? Interaction of the minK (KCNE1) protein with the poreforming Kþ channel subunits KvLQT1 (KCNQ1) and HERG (KCNH2) enhances activity of the slow (IKs) and rapid (IKr) component, respectively, of delayed rectifier potassium current. If KvLQT1 is co-expressed with minK 38G instead of minK S38, the amplitude of IKs is reduced without alterations in current kinetics. Provided that native atrial channels containing minK 38G behave similarly, the presence of the minK 38G variant will prolong the action potential (AP). Prolongation of atrial AP in patients with long QT syndrome is associated with higher incidence of polymorphic atrial tachyarrhythmias. In analogy, the presence of minK 38G could predispose to the initiation of AF. In contrast, protein levels of minK are low in patients with chronic AF, and mice that lack minK protein develop spontaneous episodes of AF associated with high IKs amplitudes and short atrial AP. Possible explanations for these apparently contradictory findings are unconcealed differences between heterologous expression systems and native atrial myocytes, accumulation of abnormal IKs current at high atrial rates, or interaction of KvLQT1 with other accessory subunits in native cells. Ion channels and their subunits are generally accepted to be organized as macromolecular complexes including regulatory proteins. Hence, by assembling with additional proteins, minK may influence function of large molecular complexes and genetically determined variant of the subunit could produce an arrhythmogenic substrate that promotes the initiation of AF. Thus, the minKassociated alterations in atrial function are complex and may predispose to NVAF even via mechanisms unrelated to IKs function. NO modulates cardiac function by nitrosylation of target proteins and by increasing cyclic guanosine monophosphate production, which in turn enhances activation of L-type Ca2þ channels. Conversely, reduced NO production may result in less Ca2þ influx via L-type Ca2þ channels and hence the shortening of atrial AP. In the presence of the eNOS 2786C allele, eNOS promoter activity is halved leading to low eNOS expression and reduced cellular NO production. Short AP due to low NO level could contribute to the associated predisposition for NV-AF in conjunction with minK 38G allele. In pigs, development of AF is in fact associated with decreased eNOS activity. As part of the ryanodine receptor Ca2þ channel (RYR2) complex, eNOS modulates intracellular Ca2þ concentration, because NO decreases the open probability of RYR2 via