Dr Rachel Myles new paper on arrhythmia mechanisms in LQTS
Initiation of ventricular arrhythmia in the acquired long QT syndrome
Congratulations to Rachel Myles and the team on their new paper which published in Cardiovascular Research. The paper provides new insights into the mechanisms of arrhythmia and could lead to new treatments for this condition.
Long QT syndrome (LQTS) carries a risk of life-threatening polymorphic ventricular tachycardia (Torsades de Pointes, TdP) and is a major cause of premature sudden cardiac death. TdP is induced by R-on-T premature ventricular complexes (PVCs), thought to be generated by cellular early-afterdepolarisations (EADs). However, EADs in tissue require cellular synchronisation, and their role in TdP induction remains unclear. We aimed to determine the mechanism of TdP induction in rabbit hearts with acquired LQTS (aLQTS).
Methods and results
Optical mapping of action potentials (APs) and intracellular Ca2+ was performed in Langendorff-perfused rabbit hearts (n = 17). TdP induced by R-on-T PVCs was observed during aLQTS (50% K+/Mg++ & E4031) conditions in all hearts (p < 0.0001 vs control). Islands of AP prolongation bounded by steep voltage gradients (VGs) were consistently observed before arrhythmia and was more closely related to the PVC upstroke than EADs, both temporally (7 ± 5 ms vs 44 ± 27 ms, p < 0.0001) and spatially (1.0 ± 0.7 vs 3.6 ± 0.9 mm, p < 0.0001). PVCs were initiated at estimated voltages of approx. -40 mV and had upstroke dF/dtmax and Vm-Ca2+ dynamics compatible with ICaL activation. Computational simulations demonstrated that PVCs could arise directly from VGs, through electrotonic triggering of ICaL. In experiments and the model, sub-maximal L-type Ca2+ channel (LTCC) block (200 nM nifedipine and 90% gCaL respectively) abolished both PVCs and TdP in the continued presence of aLQTS.
These data demonstrate that ICaL activation at sites displaying steep VGs generates the PVCs which induce TdP, providing a mechanism and rationale for LTCC blockers as a novel therapeutic approach in LQTS.
First published: 14 July 2022