Page 54 - YORAM RUDY BOOK FINAL

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causing APD prolongation. At CL=400ms the APD is prolonged by 62.3ms relative to wild-type.

As pacing rate is slowed to CL=600ms, more channels recover from inactivation between beats
increasing both background mode re-openings and the population of channels that are trapped
in the burst mode. This in turn, increases late I to cause further APD prolongation and the
Na
generation of a secondary depolarization during the late plateau phase of the action potential.

This after-depolarization is classified as early after-depolarization (EAD) because it occurs during

the action potential, before complete repolarization and return to baseline. As will be shown in
section 4.3, the prolonged APD is reflected as QT interval prolongation on the ECG, the clinical
Long QT (LQT) syndrome phenotype. In the congenital LQT3 presented here, arrhythmias occur

during sleep or relaxation, at slow heart rate (bradycardia). The simulations assume that all (100%)
Na channels in the cell are ΔKPQ mutant channels. Typically, affected individuals are
heterozygous for the mutation, so that only 50% of channels are affected. Repeating the
simulation with 50% ΔKPQ and 50% wild-type channels, EADs develop at CL=1200ms, a typical

heart rate of clinical bradycardia.

Prolongation of the action potential in regions of the heart can create spatial non-
uniformities of excitability (“dispersion of repolarization”) that provide a substrate for

unidirectional block and re-entrant arrhythmias. The EADs, in addition to delaying repolarization
and prolonging the action potential, can elicit an excitatory response that provides the trigger for
arrhythmia initiation. The ionic mechanism of EAD formation 129-132 is explored by the simulation in
Figure 2.35 ; it serves to illustrate the highly interactive environment of the cell. Action
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potentials and corresponding I Ca,L traces are shown for the last paced beat of a train of 40 beats
(green) and for an additional beat following a pause (orange). Clinically, onset of arrhythmias in
LQT syndrome often follows a pause. The pre-pause and post-pause data are overlaid in the figure.
Three EADs are generated during the plateau of the post-pause action potential. The upstroke of

each EAD corresponds to an inward peak of I Ca,L (arrows), which carries the depolarizing charge for
EAD generation. Thus, the SCN5A mutation and associated late I current prolong the action
Na
potential plateau, providing sufficient time at the appropriate potential range for I Ca,L recovery
from inactivation and reactivation. Note that completely normal L-type Ca channels, unaffected

by the mutation, carry the depolarizing charge that generates the EADs. The mutant I channels
Na
prolong the plateau phase of the action potential, thereby setting the stage for I Ca,L reactivation
and EAD generation.

Mutations in HERG and LQT2

Many mutations in HERG, the α-subunit of I , cause type 2 of the congenital long QT syndrome,
Kr
LQT2 . Of these, many are associated with abnormal trafficking and transport of the channel
134
protein to the cell membrane . Other mutations alter the channel kinetic properties. We explored
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the effects of three such mutations: T474I , R56Q and N629D , (Figure 2.36A) on the action
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135
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potential. 138