Page 122 - YORAM RUDY BOOK FINAL

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sodium channel protein accelerates fast inactivation of I , causing reduction of current. 256 In right
Na
ventricular epicardium, this occurs on the background of high I expression level. In Figure 4.7,
to
we simulate the ECG manifestation of this mutation at three levels of severity (severity increases
from left to right). The balance between outward I and inward mutant I determines the time
to
Na
course and morphology of the action potential plateau and repolarization phases, which in turn
shape the ECG waveform. In the least severe case, (left column), the ECG is characterized by ST
segment elevation with a pronounced J-wave, a morphology termed “saddleback”. With greater
severity (middle column), the T-wave becomes inverted, giving the ECG a “coved” appearance. The
T-wave inversion reflects the following action potential changes: The increased outward direction

of the balance between I and mutant (reduced) I creates a deep early repolarization (phase 1)
Na
to
notch in V of epicardial cells. The reduced V generates a large driving force to augment I Ca,L .
m
m
The increased I Ca,L prolongs the epicardial action potential beyond the repolarization time of M
cells (which normally repolarize last). This inverts the V gradient during repolarization and
m
consequently the T-wave. In the most severe case (right column), even greater shift of the balance
of currents in the outward direction results in premature epicardial repolarization and loss of the
action potential plateau. Reflecting the gradient of V , the ECG waveform assumes a “triangular”
m
shape.

The examples in this section illustrate how computational biology can be used to establish
the cellular and ion channel basis of ECG waveforms. Relating ECG patterns to action potential
properties and individual ionic currents provides a mechanistic basis for their interpretation.

The different ECG patterns (phenotypes) have clinical relevance in the context of cardiac arrhyth-
mia. 257 For example, LQT1 prolongs the QT interval without widening the T-wave, indicating that
dispersion of repolarization is not increased by the mutation. In contrast, LQT2 and LQT3 widen
the T-wave, which reflects increased dispersion. As explained in the section on conduction of the

cardiac action potential, steep repolarization gradients (large dispersion) supports the develop-
ment of reentrant arrhythmias. This difference between the LQT types might explain the lower
incidence of arrhythmias associated with LQT1 compared to LQT2 and LQT3.

Closing the Loop: From Molecule to the ECG

In section 2.6, we presented a multi-scale approach for modeling ion-channel current
(KCNQ1 and I ; Figures 2.13-2.15) starting from the movement of its molecular structure during
Ks
gating. Currents were simulated for wild-type channels and three different mutations (E160Q,
E160A, E160K) with increasing degree of current reduction. Here, we expand the scales to include
the whole-cell action potential and ECG waveforms (a model of the canine ventricular myocyte
101
was used in these simulations).