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Augmentation of late sodium current unmasks the proarrhythmic effects of amiodarone.

Abstract：

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.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Wu L,Rajamani S,Shryock JC,Li H,Ruskin J,Antzelevitch C,Belardinelli L

doi

10.1093/cvr/cvm069

subject

Has Abstract

pub_date

2008-02-01 00:00:00

pages

481-8

issue

3

eissn

0008-6363

issn

1755-3245

pii

cvm069

journal_volume

77

pub_type

杂志文章

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