In the presence of augmented late sodium current, amiodarone (30-300 nM) induced torsade de pointes in 16 of 17 isolated rabbit hearts, while higher concentrations (1-10 µM) suppressed it.
Does acute exposure to amiodarone induce torsade de pointes in an animal model with augmented late sodium current?
This preclinical model demonstrates that amiodarone has a concentration-dependent biphasic effect, inducing torsade de pointes when late sodium current is augmented, and suppressing it at higher concentrations.
p-value: p=<0.01
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 electrocardiogram were recorded in female rabbit isolated hearts. Ion channel currents were measured in human embryonic kidney cells expressing SCN5A Na+ and HERG K+ 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 MAPD(90) 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 concentration to 1-10 microM abbreviated MAPD(90) 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 K+ and late Na+ currents with IC50s of 0.8 +/- 0.1 and 3.0 +/- 0.9 microM, respectively. CONCLUSION: In hearts in which late INa is augmented to mimic congenital or acquired pathological conditions, amiodarone has a concentration-dependent biphasic effect to induce and then suppress arrhythmic activity, secondary to inhibition of HERG K+ and late Na+ currents. This is the first preclinical model demonstrating the potential for amiodarone to induce TdP.
Wu et al. (Mon,) conducted a other in Torsade de pointes (TdP) (n=17). Amiodarone vs. Acute amiodarone alone / Baseline was evaluated on Induction of Torsade de pointes (TdP) and changes in MAPD90 (p=<0.01). In the presence of augmented late sodium current, amiodarone (30-300 nM) induced torsade de pointes in 16 of 17 isolated rabbit hearts, while higher concentrations (1-10 µM) suppressed it.