Page 33 - YORAM RUDY BOOK FINAL

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We developed a model of canine Pcell that represents its unique ultrastructure and
electrophysiological properties . Details of the model and simulation studies of the rate
93
dependence of the AP and CaT can be found in the original publication . Here, we reproduce
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results related to the greater vulnerability of Pcell, compared to Vcell, to arrhythmic behavior. In
Figure 2.19, Pcell or Vcell are paced at CL=300ms. After cessation of pacing, in the presence of

increased RyR2 sensitivity, Pcell develops spontaneous delayed after depolarizations (DADs) and
triggered APs 14a,90 , whereas Vcell remains quiescent (Panel B). In Panel C, selected ionic currents or
concentrations (I CaT , Ca current through T-type Ca channel; I NaL ; I ; I , the “funny” hyperpolarization
K1
f
activated current; and [Ca ] NSR , Ca concentration in network SR) are modified to be “ventricular
2+
2+
like”. Specifically, relative to Pcell, Vcell has a much smaller I NaL , larger I , which stabilizes the rest
K1
potential, smaller SR Ca content, and no I CaT and I currents. Block of I CaT reduced the number of
f
spontaneous events (only three spontaneous triggered APs), whereas block of I NaL eliminated all
triggered APs. A 50% increase of I or block of I also eliminated triggered APs, as did 30%
f
K1
reduction of SR Ca content. It follows that Pcell vulnerability to DADs and triggered activity is
attributable to: (1) higher SR Ca content than Vcell; (2) membrane ion-channel profile that
reduces excitation threshold and resting membrane potential stability; (3) presence of
depolarizing ion channels that promote AP depolarization and triggered activity (I CaT and

large I NaL ). The results of these simulations predict that Pcell should play an important role in
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) , where mutations in RyR2 or
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Calsequestrin render the ryanodine receptor hypersensitive.

Figure 2.19. Delayed afterdepolarizations
(DAD) and triggered activity. A. After
cessation of steady-state pacing at
CL= 300ms, no spontaneous activity is
observed in Pcall or Vcell under control
conditions. B. With increased RyR2
sensitivity, Pcell develops DADs and
triggered APs, whereas Vcell remains
quiescent. C. Ionic currents or
concentrations in Pcell are adjusted
either individually or together (combined)
to resemble their Vcell counterparts. *
Triggered AP; # subthreshold DAD.
From Li and Rudy [93]. Reproduced
with permission from Wolters Kluwer
Health, Inc.