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.