L-type calcium current recovery versus ventricular repolarization: preserved membrane-stabilizing mechanism for different QT intervals across species

BackgroundLong QT syndrome is associated with early afterdepolarization (EAD) that may result in torsade de pointes (TdP). Interestingly, the corrected QT interval seems to be proportional to body mass across species under physiologic conditions.ObjectiveThe purpose of this study was to test whether recovery of L-type calcium current (ICa,L), the primary charge carrier for EADs, from its inactivated state matches ventricular repolarization time and whether impairment of this relationship leads to development of EAD and TdP.MethodsTransmembrane action potentials from the epicardium, endocardium, or subendocardium were recorded simultaneously with a transmural ECG in arterially perfused left ventricular wedges isolated from cow, dog, rabbit, and guinea pig hearts. ICa,L recovery was examined using action potential stimulation in isolated left ventricular myocytes.ResultsThe ventricular repolarization time (action potential duration at 90% repolarization [APD90]), ranging from 194.7 ± 1.8 ms in guinea pig to 370.2 ± 9.9 ms in cows, was linearly related to the thickness of the left ventricular wall among the species studied. The time constants (τ) of ICa,L recovery were proportional to APD90, making the ratios of τ to APD90 fall into a relatively narrow range among these species despite markedly different ventricular repolarization time. Drugs with risk for TdP in humans were shown to impair this intrinsic balance by either prolongation of the repolarization time and/or acceleration of ICa,L recovery, leading to the appearance of EADs capable of initiating TdP.ConclusionAn adequate balance between ICa,L recovery and ventricular repolarization serves as a “physiologic stabilizer” of ventricular action potentials in repolarization phases.