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Figure 4.7. I mutation and the Brugada syndrome. Three levels of severity are simulated, with
Na
severity increasing from left to right. Effect of the mutation on I function is introduced by accel-
Na
erating its fast inactivation (decreasing the time constant of fast inactivation, τ ). The pseudo-ECG
h
(bottom) shows the characteristic “saddleback”, “coved” and “triangular” morphologies, reflecting
the level of severity. Reproduced from Gima and Rudy [247] with permission from Wolters Kluwers
Health, Inc.

Figure 4.8 shows the simulated action potential and I currents (wild type and mutant)
Ks
during its time course at slow (A, CL=1000ms) and fast (B, CL=300ms) rates. The most severe LQT1
mutation (E160K, blue) results in total absence of I current during the action potential and
Ks
consequently in a major prolongation of the action potential duration. The E160Q and E160A
mutations (green and purple, respectively) result in slower activation of the mutant I current
Ks
and also prolong the action potential. A mutation in KCNE1 (the β-subunit of I ), L51H, 258,259 is also
Ks
simulated (orange; the LQT syndrome linked to KCNE1 mutations is LQT5). This mutation causes
more moderate action potential prolongation. Note that the mutation-induced action potential
prolongation increases at slow heart rates (panel C), a hallmark of LQT phenotype. On the

computed ECG waveform (pseudo-ECG, panel D), the QT interval is prolonged for all mutations
relative to wild-type, with E160K showing the most severe and L51H the least severe QT interval
prolongation, consistent with clinical observations in patients .
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