Alternating Cycle Lengths Increases Dispersion of Action Potential Durations (APD) in Transgenic Rabbit Model of Long QT Syndrome Type 2

Long QT syndrome Type 2 (LQT2) is a congenital disease with abnormal prolongation of APD and sudden cardiac death (SCD) due to polymorphic ventricular tachycardia (pVT). These arrhythmias are often preceded by a characteristic initiation mode of short-long-short alternating cycle lengths (CL) in surface electrocardiograms. We hypothesized that alternating CLs in LQT2 cause increased APD dispersion, which may promote reentry formation.We used transgenic LQT2 rabbits (lacking, IKr) to investigate the potential role of alternating CLs on APD dispersion. Hearts (n=4 & 5 for littermate control (LMC) and LQT2) were perfused and action potentials were recorded with voltage sensitive dye (di-4 ANEPPS) and CMOS camera (100x100 pixels, 1000 f/s) from anterior region of the heart. Hearts were stimulated at computer-generated random intervals (ranging from its refractory period plus 50 ms, typically 220-270 ms) and the pattern of stimulation logic pattern that creates enhanced APD dispersion was identified from LQT2 and LMC.While APD dispersion from LMC had no clear patterns (S1/S2/S3=232/224/225 ms) preceding enhanced APD dispersion (n=4/4), enhanced APD dispersion from LQT2 consistently showed alternating CL dynamics (S1/S2/S3= 253/250/262 ms, with increased APD dispersion from 19±10 to 40±1 ms, n=5/5). The detail analysis shows that spatially heterogeneous APD restitution in LQT2 promoted APD dispersion. In addition, lack of IKr in LQT2 increased cardiac memory effect; APD was dependent on the short-term of heart rate variation with higher coefficients from previous CLs (S1/S2 = 0.67/0.27 in LQT2 vs. 0.31/0.08 in LMC) due to slow kinetics of remaining repolarizing current (IKs), enhancing APD dispersion under alternating CLs.In conclusion, combined with heterogeneous restitution and memory effect of APD, short-long CLs in LQT2 may precipitate polymorphic VTs by creating large APD dispersion.