Augmentation of late sodium current unmasks the proarrhythmic effects of amiodarone

Aim Clinical use of amiodarone is associated with occasional development of torsade de pointes (TdP). However, preclinical models have failed to demonstrate the proarrhythmic potential of amiodarone. The objective of this study was to reveal and explain the pro- and anti-arrhythmic effects of acute exposure to amiodarone in an animal model. Methods and results Endo- and epicardial monophasic action potentials (MAPs) and 12-lead electro-cardiogram were recorded in female rabbit isolated hearts. Ion channel currents were measured in human embryonic kidney cells expressing SCN5A Naþ and HERG Kþ channels. Acute amiodarone alone caused an insignificant increase in duration of MAP (MAPD90) without causing TdP. In the presence of 3 nM sea anemone toxin (ATX-II), amiodarone (1–30 nM) prolonged MAPD90 from 217+5 to 250+ 8 ms (n 16, P, 0.01), increased transmural dispersion of repolarization (TDR) from 59+9 to 70+ 10 ms and beat-to-beat variability (BVR) of MAPD90 from 0.75+0.03 to 1.06+0.13 ms (P, 0.05). At 30–300 nM, amiodarone induced TdP in 16 out of 17 hearts. A further increase of amiodarone concen-tration to 1–10 mM abbreviated MAPD90 to 211+9 ms, decreased BVR to 0.5+0.01 ms, decreased TDR (n 7, P, 0.05), and suppressed TdP. Amiodarone inhibited HERG Kþ and late Naþ currents with IC50s of 0.8+0.1 and 3.0+0.9 mM, respectively