Electrical Remodeling

Alterations in myocyte ion channel properties have long been known to precede fibrotic remodeling and predominate in the domestication of AF in its early stages. In early animal models, artificially maintaining AF through rapid atrial pacing enhanced AF inducibility and a tendency to sustain (13,14). Pronounced reduction in atrial refractory properties and reverse adaptation of repolarization to rate were observed to underlie these phenomenon. In the animal models, significant alterations in repolarization properties are observed early in AF, implying acute changes in ion channel function and expression. For example, in the goat model of pacing-induced AF, significant reductions in atrial ERP are seen within 24 hours, and peak at 2-3 days.
Valuable insights into the relative contribution of the various ion channels have been garnered from genetic studies. Gain of function mutations in the KCNQ1 gene encoding the pore-forming subunit of the voltage-gated potassium channel Kv7.1 several other beta accessory subunit genes have been linked to familial or early-onset lone AF (63). Genetic mutations have similarly been reported in numerous other members of the cardiac potassium channel superfamily. Both gain and loss of function mutations have been associated with a predisposition to AF, and in some cases the pathological relevance of the mutation remains yet to be elucidated (64,65). Frequently however, these mutations seem to result in abbreviation of the action potential duration, promoting re-entry and arrhythmia maintenance. Loss of function mutations in theSCN5A gene encoding the alpha subunit of the voltage-gated sodium channel, NaV1.5, or in the genes encoding one of its four beta subunits would be anticipated to result in conduction slowing (66,67). Such mutations, in addition to gain of function mutations, have been linked to cases of AF, although the electrophysiological phenotype have not been characterized.
Mutations such as those described are thought to account for a small proportion of AF cases overall, however atrial electrophysiological properties observed in most cases appear phenotypically analogous. Consistent with findings in animal models, time-dependent alterations in atrial activation and repolarization characteristics have been observed in human studies. Thus pacing-induced AF was associated with early reductions in atrial effective refractory periods, which recovered to baseline levels shortly after the restoration of sinus rhythm, in keeping with reversible modulation of ion channel function (68). Such shortening of atrial refractory periods has similarly been associated with PsAF (69). Abbreviation of the action potential duration has also been noted in the context of PsAF in several studies (70–72). The shortening of atrial refractory periods, action potential duration, and its adaptation to heart rate, have been attributed to a reduction inI Ca, secondary to reduced expression of L-type calcium channels (73,74), and modification in the expression and functional properties of a variety of potassium channels. The latter include reductions in the transient outward potassium current (I to) (70,72) and upregulation of the constitutively active G-protein gated potassium channel,I KAch (75). Reductions in the inward sodium current through the voltage-gated sodium channel,I Na, would be anticipated to contribute to conduction slowing, however data evaluating this is limited, and no changes in the expression of this ion channel have been reported to date (70).
It should be noted that much of the data pertaining to the molecular correlates of electrical remodeling are conflicting and difficult to reconcile. Additionally, the functional consequences of changes in individual ion channel expression and function often appear subtle, and in isolation insufficient to promote arrhythmogenesis. It is likely that it is the synergistic effect of a collection of alterations that supports arrhythmia initiation and maintenance (76,77). Additionally, some discrepancies in the data may reflect the patchy nature of remodeling across the atrial landscape.