Spontaneous initiation of premature ventricular complexes and arrhythmias in type 2 long QT syndrome

Abstract

The occurrence of early afterdepolarizations (EADs) and increased dispersion of repolarization are two known factors for arrhythmogenesis in long QT syndrome. However, increased dispersion of repolarization tends to suppress EADs due to the source-sink effect, and thus how the two competing factors cause initiation of arrhythmias remains incompletely understood. Here we used optical mapping and computer simulation to investigate the mechanisms underlying spontaneous initiation of arrhythmias in type 2 long QT (LQT2) syndrome. In optical mapping experiments of transgenic LQT2 rabbit hearts under isoproterenol, premature ventricular complexes (PVCs) were observed to originate from the steep spatial repolarization gradient (RG) regions and propagated unidirectionally. The same PVC behaviors were demonstrated in computer simulations of tissue models of rabbits. Depending on the heterogeneities, these PVCs could lead to either repetitive focal excitations or reentry without requiring an additional vulnerable substrate. Systematic simulations showed that cellular phase 2 EADs were either suppressed or confined to the long action potential region due to the source-sink effect. Tissue-scale phase 3 EADs and PVCs occurred due to tissue-scale dynamical instabilities caused by RG and enhanced L-type calcium current (I), occurring under both large and small RG. Presence of cellular EADs was not required but potentiated PVCs when RG was small. We also investigated how other factors affect the dynamical instabilities causing PVCs. Our main conclusion is that tissue-scale dynamical instabilities caused by RG and enhanced I give rise to both the trigger and the vulnerable substrate simultaneously for spontaneous initiation of arrhythmias in LQT2 syndrome.

Determinants of early afterdepolarization properties in ventricular myocyte models

“…For example, in an early experimental study [17], Damiano and Rosen showed that phase-2 EADs cannot propagate as premature ventricular complexes (PVCs) while phase-3 EADs can propagate as PVCs. This was also shown in our simulation studies [18][19][20]. Therefore, understanding what determine the EAD amplitude and takeoff potential may provide insights into EAD propagation to produce PVCs.…”

“…Cm is the membrane capacitance which was set as Cm=1 F/cm 2 . We simulated six ventricular AP models: the 1991 Luo and Rudy (LR1) guinea pig model [26]; the 1994 Luo and Rudy (LRd) guinea pig model in a modified version [27]; the UCLA (HUCLA) rabbit model with modifications by Huang et al [20]; the 2004 ten Tusscher et al (TP04) human model [28]; the Grandi et al (GB) human model [24]; and the O'Hara et al (ORd) human model [29].…”

“…We first made theoretical predictions of the EAD properties using the 1991 Luo and Rudy (LR1) model [26] based on our previous bifurcation theory of EADs [4]. We then carried out computer simulations using physiologically more detailed ventricular AP models [18,20,24,[27][28][29] to verify the theoretical predictions. In computer simulations, we also used parameter sets randomly drawn from assigned intervals so that large parameter ranges are explored to ensure generality of the simulation results.…”

Update on long QT syndrome

“…Despite the great advances in understanding the genetic basis of LQTS, the mechanisms resulting in arrhythmia susceptibility are less well understood. The occurrence of early/late afterdepolarizations and increased dispersion of repolarization are thought to play a role in arrhythmogenesis . In LQTS, the decrease in net outward current leads to increased calcium uptake via voltage dependent Ca 2+ channels on the myocardial cell membrane.…”

“…The occurrence of early/late afterdepolarizations and increased dispersion of repolarization are thought to play a role in arrhythmogenesis. 20 In LQTS, the decrease in net outward current leads to increased calcium uptake via voltage dependent Ca 2+ channels on the myocardial cell membrane. This net increase in inward Ca 2+ flow leads to Ca 2+ -dependent calcium release from the sarcoplasmic reticulum in the submembrane intracellular space which in turn leads to new Na + inward current via Ca 2+ -Na + exchange, triggering afterdepolarization-mediated premature ventricular complexes, which act as triggers of the arrhythmia.…”