The Mechanism of Pause-Induced Torsade de Pointes in Long QT Syndrome

Jinqiu Liu, M.D.; Kenneth R. Laurita, Ph.D.


J Cardiovasc Electrophysiol. 2005;16(9):981-987. 

In This Article

Mechanisms of TdP

Despite our understanding of pause-induced changes in the electrophysiological substrate, the exact mechanism of TdP induction is not completely clear. It is generally believed that spontaneous TdP can arise from an EAD-induced triggered beat that occurs near the endocardium (e.g., Purkinje fibers) and encounters intense repolarization gradients in the midmyocardial region resulting in unidirectional block,[12] an important requirement for reentrant excitation. Alternatively, there is a significant body of work that suggests an EAD can arise in M-cells where APD is significantly prolonged under LQTS conditions.[4,30] One potential problem, however, with this paradigm is that if an EAD-induced triggered beat occurs where APD is longest, then how can it form unidirectional block if all other regions have already recovered? The most intriguing finding in our study is that the breakthrough site (not necessarily the origin) of EAD-induced triggered activity occurred not where APD was longest or shortest, but where repolarization gradients were most intense (Figs. 5 and 6). This is an unlikely location, because there is little data suggesting that EADs occur where repolarization gradients are most intense. One possibility is that a triggered beat originates where APD is longest (M-cell) but in many cases below the mapping field. Then, it breaks through were the repolarization gradient is largest because this is the region that is closest to the site of origin (M-cell) but also partially excitable. The reason why breakthrough does not occur where recovery is earliest (shortest APD) is not clear, but it could be that this region is further away from the site of origin (M-cell). It is also possible that heterogeneous Cx43 expression may play a role in the successful propagation of triggered beats.[31] In either case, an EAD-triggered beat seems to propagate along the maximum repolarization gradient, where it is more likely to form unidirectional block. This suggests a mechanism by which M-cells play an important role in both the origin of EAD-induced triggered activity and unidirectional block during a short-long cycle length sequence.

Action potentials were recorded from the transmural surface. As a result, we could not confirm the exact location of EAD-induced triggered activity and the pattern of APD below the mapping surface. However, our data suggest that the site of EAD origin was not far from the breakthrough site. Based on the ECG QRS onset and the timing of breakthrough, a delay of no more than 10 msec was observed. Another limitation is that these experiments were performed in wedge preparations that lack an intact normal Purkinje system and normal contraction. Therefore, the full effect of Purkinje fibers or contraction on APD, EAD generation, and TdP may be underestimated. Finally, the influences of neurohumoral factors on pause-dependent TdP were excluded from this study.[32,33] This may be why few EADs, EAD-induced triggered activity, and episodes of TdP were observed under LQT2 condition in our study. Nevertheless, most of our findings were reported from the LQT3 model. In LQT3 syndrome, cardiac events mostly occur during rest and sleep when sympathetic tone is low and not expected to significantly influence TdP.[32]