Page 69 - Cardiac Electrophysiology | A Modeling and Imaging Approach

P. 69
Pathologies such as heart failure may involve detubulation of the myocyte T-tubule

network, changes in dyadic structure, and impaired functional coupling between LCCs and
RyR2s . These subcellular local changes can disrupt normal whole-cell global function. We
170
examined the global consequences of local dyadic changes . Simulations included structural
162
modifications to the dyads (changes in dyadic volume and number of LCCs/RyR2s, and impaired
interdyad coupling), and impaired CSQN function. Here, we reproduce two such simulations as
examples:

1. Impaired interdyad coupling. In the model, each dyad communicates with its neighboring

dyads via Ca diffusion. When interdyad coupling was impaired and the number of LCCs in a dyad
was reduced from 15 to 7, SR Ca release became asynchronous (Figure 2.47, black line) resulting in
a smaller peak and slower time to peak of CaT.

2. Impaired CSQN function. Figure 2.48 shows the effects of impaired CSQN function as
regulator of RyR2 openings, in the presence of intact (Figure 2.48, A and B) or impaired (Figure
2.48, C and D) CSQN buffering capacity. Multiple diastolic Ca release events in the form of Ca
sparks (yellow arrows) and Ca waves (white arrows) occur when the CSQN buffer function is

intact (Figure 2.48A). Figure 2.48B shows that the dyad reactivates during the AP (#) and
activates spontaneously during diastole (*), indicating abnormal restitution of SR Ca release. In a
paced control myocyte model, Ca sparks rarely occur in diastole, due to the refractoriness of the

RyR2s. In a quiescent myocyte, the spontaneous Ca spark frequency is 40/cell/s, which is similar
to the experimentally recorded frequency in guinea pig . When CSQN buffer is also impaired,
171
long lasting Ca release events occur in few dyads, indicating a defective termination process of
Ca release (white arrows in Figure 2.48C). Ca sparks occur in diastole (yellow arrows). However,
Ca waves do not develop, because in the absence of CSQN buffer, the JSR Ca content and the

amount of released Ca is small and insufficient to trigger release from adjacent dyads to generate
a propagating wave. Figure 2.48D shows Ca dyad in one of the dyads. The dyad reactivates during
d
the AP (#) and can also activate spontaneously (*) in diastole, indicating that both abnormal

termination and abnormal restitution are present at the dyadic level. The long lasting release
events last longer than 3.8s.