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Cardiovascular Research Advance Access [Accepted Manuscript] published online on November 13, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm069
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Augmentation of Late Sodium Current Unmasks the Proarrhythmic Effects of Amiodarone

Lin Wu, MD, Sridharan Rajamani, PhD, John C. Shryock, PhD, Hong Li, MS, Jeremy Ruskin, MD, Charles Antzelevitch, PhD and Luiz Belardinelli, MD

Department of Pharmacological Sciences, CV Therapeutics, Inc. (L.W., S.R., J.S., H.L., L.B.), Palo Alto, CA, USA; Cardiac Arrhythmia Service, Massachusetts General Hospital (J.R.), Harvard Medical School, Boston, MA, USA; Masonic Medical Research Laboratory (C.A.), Utica, NY, USA

Corresponding author: Lin Wu, MD, Department of Pharmacological Sciences, CV Therapeutics, 3172 Porter Drive, Palo Alto, CA 94304, USA. Fax number: (650) 475-0393; Telephone number: (650) 384-8624; E-mail: lin971{at}yahoo.com

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: Endo- and epicardial monophasic action potentials (MAPs) and 12-lead ECG were recorded in female rabbit isolated hearts. Ion channel currents were measured in human embryonic kidney cells expressing SCN5A Na+ and HERG K+ channels.

Results: 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 concentration to 1-10 µM 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 K+ and late Na+ currents with IC50s of 0.8±0.1 and 3.0±0.9 µM, 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.

KEYWORDS antiarrhythmic agents; arrhythmia (mechanism); ion channels; long QT syndrome; membrane potentials

Time for primary review: 21


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Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
L. Wu, S. Rajamani, H. Li, C. T. January, J. C. Shryock, and L. Belardinelli
Reduction of repolarization reserve unmasks the proarrhythmic role of endogenous late Na+ current in the heart
Am J Physiol Heart Circ Physiol, September 1, 2009; 297(3): H1048 - H1057.
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