Page 100 - YORAM RUDY BOOK FINAL

P. 100
When I is compromised, the action potential upstroke is determined by the delicate
Na
balance between inward (depolarizing) I and outward (repolarizing) I . The role of I is
to
Na
to
examined in Figure 3.19A (bottom panel) and Figure 3.19C. When I conductance G (membrane
to
to
density) was reduced by 50% in the mutant fiber, the conduction delay at CL=1,000 msec was
eliminated and continuous, I -supported conduction was restored. Similar reduction of G had
to
Na
no effect on the nature and velocity of conduction at CL=300 msec. At this fast pacing rate, I
to
could not recover completely from inactivation between beats and was therefore reduced during
the action potential even with full membrane density (G =100%). On the background of reduced
to
I at the fast pacing rate, mutant I was sufficient to sustain conduction. At slow rate, I recovered
to
to
Na
completely between beats and phase-0 conduction failed, transitioning to phase-2 conduction
following a long delay at the M-epicardium transition zone.

The results of these simulations have clinical implications. They suggest that reduction of

I by drug block or by chronotropic intervention aimed at keeping the heart rate sufficiently fast,
to
can prevent long conduction delays and restore I -supported conduction in patients with the
Na
F20004L mutation and associated Brugada phenotype. The important role of I Ca,L in supporting
conduction in this setting suggests that I Ca,L augmentation can enhance and stabilize conduction.

Indeed, a consensus report on Brugada syndrome 228 confirms that I antagonists, I Ca,L agonists,
to
or a combination of both can be therapeutic. The simulation results also provide a mechanistic
explanation to the rate dependence of the F2004L phenotype, which expresses clinically at slow
heart rates (bradycardia).

It is interesting and instructive to compare the F2004L mutation simulated here to
another SCN5A mutation, the 1795insD, both associated with the Brugada syndrome phenotype
of ST segment elevation on the ECG. The sodium channel kinetic changes are specific to each

mutation, but both mutations cause a loss of channel function and reduced I current. As will be
Na
formulated mathematically and explained in section 4, ST-segment elevation in the ECG reflects
a spatial gradient of V , the transmembrane potential, during the action potential plateau and/or
m
repolarization phases. The 1795insD mutation slows recovery from inactivation of I , causing
Na
preferential reduction of I at fast rate because of incomplete recovery between beats. 229,230 On
Na
the background of outward I , premature action potential repolarization occurs. However, this
to
effect is spatially heterogeneous because of the variable density of I across the myocardium,
to
particularly across the ventricular wall. This creates a spatial repolarization gradient and

consequently a spatial V gradient, which reflects as ST segment elevation on the ECG. Thus, in
m
the case of the 1795insD mutation, repolarization gradients and ST elevation result from direct
effect of the mutant I on action potential repolarization. In contrast, I reduction by the F2004L
Na
Na
mutation creates repolarization gradients indirectly, by affecting action potential propagation and
introducing conduction delays at slow heart rate.