Voltage/Calcium Uncoupling Underlies Sustained Torsade de Pointes Ventricular Tachyarrhythmia in an Experimental Model of Long QT Syndrome

Figures

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  FIGURE 1. The figure illustrates simultaneous Vm (in black) and Cai (in red) signals from the same pixel during control (A) and following AP-A perfusion (B,C). The heart was paced at a CL of 750 ms. The Cai transient followed the Vm by approximately 10–15 ms. (B) Was obtained 3 min following AP-A perfusion and shows that both Vm and Cai durations increased by approximately 40–50%. It also shows the development of a moderate degree of alternans of both amplitude and duration of the Cai transient but no detectable change in the Vm duration. (C) Was obtained following 10 min of AP-A perfusion and illustrates the development of significant alternans of the amplitude and duration of the Cai transient. The Cai transient alternans was associated with significant alternans of Vm duration at plateau level (arrow). A premature beat seemed to arise from the plateau level and initiated a non-self-terminating VT.

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  FIGURE 2. The figure was obtained from a different experiment and illustrates simultaneous Vm and Cai transient recordings from selected pixels in the epicardial optical window. The recordings in (A–C) are consecutive with a few minutes apart. The recordings illustrate a common observation in the AP-A guinea pig surrogate model of LQT3, i.e., the frequent development of ST/VT episodes of variable duration (A,B) before the development of NST/VT (C). An interesting observation in this model shown clearly in (A) is that the first beat following the end of a ST/VT shows significant prolongation of Vm duration and a large increase in both amplitude and duration of the Cai transient. Because of the marked prolongation of the Cai transient, the transient of the next paced beat arose before return to baseline of the preceding Cai transient and initiated Cai transient alternans associated with moderate alternation of Vm duration.

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  FIGURE 3. (A) Illustrates a running entropy measure during the ST/VT shown in Figure 2B. This was constructed by calculating the entropy value of Vm and Cai separately at 160 ms intervals. The recording shows the entropy value was close to zero during the basic stimulated beats (first 2 beats and last 2 beats in the recording). During the VT episode the entropy value of both Vm and Cai increased but remained closely coupled reflecting a low degree of entropy difference. We utilized the difference in entropy values, Ed, as measure of the difference in complexity between Vm and Cai dynamics in this system. (B) Illustrates the wave front topology during the early phase of the ST/VT by showing Vm and Cai maps in 4 consecutive frames at 20 ms intervals starting 220 ms from the onset of VT (see arrow). The Vm and Cai activation maps are concordant with the Cai activation wave front closely following the Vm wave front.

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  FIGURE 4. The figure illustrates the Vm/Cai kinetics during the early phase of the NST/VT shown in Figure 1C. (A) Illustrates the running entropy during the NST/VT. The entropy values of both Vm and Cai increased. However, in contrast to the ST/VT, the two entropy values diverged from each other, reflecting a high degree of discordant entropy. (B) Illustrates the Vm and Cai maps in 4 consecutive frames at 20 ms intervals starting at 200 ms from the time of onset of VT (approximately the same as the time frame selected for the ST/VT in Figure 3, see arrow). The Vm and Cai activation maps show discordant wave front topology with evidence of wave break in both the Vm and Cai maps.

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  FIGURE 5. The figure was obtained from a different experiment. Top panel shows simultaneous Vm (black) and Cai (red) recording of spontaneous ventricular rhythm followed by an early premature beat (first arrow) that initiated a 560 ms episode of fast polymorphic VT at an average CL of 130 ms. The polymorphic VT changed into a monomorphic VT at a CL of 200 ms that lasted for 10 s before it spontaneously terminated. The lower two panels show simultaneous Vm and Cai wave fronts from the optical field at 50 ms intervals during the first 400 ms of the polymorphic episode (marked by the two arrows). There was no correlation between the Vm and Cai with frequent wave break of both activation wave fronts reflecting a high degree of Ed. The wave break started immediately after the initiating premature beat in the Vm recording.

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  FIGURE 6. It was obtained from the same experiment shown in Figure 5. The top panel is similar to the top panel shown in Figure 5. The two lower panels show simultaneous Vm and Cai wave fronts from the optical field covering 400 ms of the monomorphic VT at 50 ms intervals (the section marked by the two arrows). It shows that the Cai activation wave front regularly followed the Vm wave front with no evidence of wave break reflecting a lower degree of Ed.

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  FIGURE 7. Bar graphs of means and standard deviations of Ed for the basic rhythm preceding VT episodes (B), ST VTs (S), and NSTVT (NST). The Ed values during the basic rhythm were consistently close to zero (0.08). The Ed values for NST/VTs (0.89 ± 0.21) were significantly higher than the Ed values for ST/VTs (0.33 ± 0.18); (p < 0.001).