Page 57 - Cardiac Electrophysiology | A Modeling and Imaging Approach

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The simulations of Figure 2.37 compare the mutant action potentials to wild-type. Each

mutation is simulated by a modified Markov model of I that incorporates the mutation induced
Kr
kinetic changes. This model is then introduced into the LRd ventricular myocyte. The figure
displays the I current and occupancies of channel states during the action potential. For wild-
Kr
type channels (left column), the dynamic interplay between rapid inactivation (O to I) and gradual

recovery from inactivation (I to O) during the action potential plateau generates a pronounced
late peak of open-state occupancy (O; arrow). This causes I to peak at the late plateau phase,
Kr
when it is most effective in influencing repolarization and action potential duration.

The T474I mutation causes only a minor prolongation of the action potential relative to
wild-type. The prolongation is caused by the reduced I current density. The mutation-induced
Kr
kinetic change (negative shift of activation) affects I only at the early action potential phase
Kr
(because it modifies activation), when it has a minimal effect on repolarization and APD. The late

plateau peak of open state occupancy is unaffected by the mutation (Figure 2.37F, arrow),
generating a maximum I current late in the action potential, when its effect on repolarization
Kr
and APD is maximal (similar to wild-type).

In contrast to the T474I mutation, R56Q exerts its effect during the late plateau and
repolarization phases of the action potential. This mutation accelerates deactivation (transition
from O to C1), which removes the late peak of open-state occupancy (Figure 2.37F) and
consequently the late peak of macroscopic I (Figure 2.37B). As a result, I is reduced when it
Kr
Kr
normally plays a major role in repolarization and APD is greatly prolonged.

The two mutations discussed above are classified as “loss of function” mutations
because they reduce I current. Being an outward repolarizing current, its reduction causes
Kr
delayed repolarization and prolongation of APD. For an inward depolarizing current, an increase
in magnitude prolongs the APD. The ΔKPQ mutation augments late I and serves as an example
Na
of a “gain of function” mutation. Thus, it is accepted that loss of function of a repolarizing current
(e.g., I or I ) or gain of function of a depolarizing current (e.g., I or I Ca,L ) leads to action potential
Na
Kr
Ks
prolongation and LQT. The N629D mutation challenges this classification because the
mutation-induced kinetic changes (loss of inactivation and loss of K selectivity) augment,
+
rather than reduce the current. The simulations in Figure 2.38 help to resolve this seemingly
paradoxical observation. The reduced channel selectivity permits Na permeation with a relative
+
selectivity P /P = 0.65. This elevates the reversal potential of I to -13 mV, which is in the range of
Kr
K
Na
the action-potential plateau. As a result, I becomes an inward (depolarizing) current below -13mV
Kr
(arrows in Figure 2.38A), prolonging greatly the action potentials of epicardial cells (by 80 ms). In
M cells that have a smaller I , the inward phase of mutant I is sufficient to cause EADs (Figure
Ks
Kr
2.38B).