Page 30 - YORAM RUDY BOOK FINAL

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Experiments in isolated nonfailing human ventricular endocardial myocytes showed EADs
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when paced very slowly (CL=4000ms) in the presence of the I blocker dofetilide (0.1 µM, ~ 85%
Kr
I block). Figure 2.16A top row, shows the experimental results (left) and simulations of the same
Kr
protocol using the ORd model (right). The bottom row shows simulated results from two other
human models – GB and TP . As in the experiments, the ORd model produced an EAD when
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paced at slow rate (CL=4000ms) with 85% block of I . The other models failed to produce an EAD
Kr
even with complete (100%) block of I , Fig. 2.16B shows the mechanism of EAD formation. I block
Kr
Kr
induced prolongation of the plateau, allowing sufficient time at plateau potentials for I CaL recovery
and reactivation. When I CaL recovery was prevented in the simulation, the EAD was

eliminated. This mechanism is the same as shown previously in other species .
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Figure 2.16. Early afterdepolarizations (EADs) in human ventricular myocyte. A, top left.
Experiments in isolated nonfailing human endocardial myocytes from Guo et al. showed EADs
87
with slow pacing (CL=4000ms) in the presence of I block (0.1 µM dofetilide, ~85% I block). A, top
Kr
Kr
right. Following the experimental protocol, (CL=4000ms, 85% I block) the ORd model
Kr
accurately produced a single large EAD. A, bottom. Other human ventricular cell models (GB left
and TP right) failed to generate EADs even with 100% I block. B. EAD mechanism. APs are on
Kr
top. I CaL (black) and I CaL recovery gate (gray) are below. Slow pacing alone did not cause an EAD
(left). Slow pacing with I block (85%) caused an EAD (solid line, right). The EAD was depolarized
Kr
by I CaL reactivation during the slowly repolarizing AP plateau (solid line, solid arrows). When I CaL
recovery was prevented, the EAD was eliminated (dashed line, dashed arrow). From O’Hara et. al.
[18]. Reproduced under PLOS ONE Creative Commons Attribution (CC BY) license.