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Mechanisms of Arsenic-Induced Prolongation of Cardiac Repolarization

Rammelkamp Center for Education and Research, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio (E.F., Y.A.K., A.T.D., L.W., A.M.B.); Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio (C.O.-P.); and ChanTest, Inc., Cleveland, Ohio (P.H., B.A.W.)

Arsenic trioxide (As₂O₃) produces dramatic remissions in patients with relapsed or refractory acute promyelocytic leukemia. Its clinical use is burdened by QT prolongation, torsade de pointes, and sudden cardiac death. In the present study, we analyzed the molecular mechanisms leading to As₂O₃-induced abnormalities of cardiac electrophysiology. Using biochemical and electrophysiological methods, we show that long-term exposure to As₂O₃ increases cardiac calcium currents and reduces surface expression of the cardiac potassium channel human ether-a-go-go-related gene (HERG) at clinically relevant concentrations of 0.1 to 1.5 µM. In ventricular myocytes, As₂O₃ increases action potential duration measured at 30 and 90% of repolarization. As₂O₃ interferes with hERG trafficking by inhibition of hERG-chaperone complexes and increases calcium currents by a faster cellular process. We propose that an increase in cardiac calcium current and reduced trafficking of hERG channels to the cell surface cause QT prolongation and torsade de pointes in patients treated with As₂O₃. Our results suggest that calcium-channel antagonists will be useful in normalizing QT prolongation during As₂O₃ therapy. As₂O₃ is the first example of a drug that produces hERG liability by inhibition of ion-channel trafficking. Other drugs that interfere with proteins in the processing pathway of cardiac ion channels may be proarrhythmic for similar reasons.

Address correspondence to: Dr. Eckhard Ficker, Rammelkamp Center, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109. E-mail: eficker{at}metrohealth.org

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