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(Circulation. 2008;118:981-982.)
© 2008 American Heart Association, Inc.

Editorial

Repolarization Reserve

A Moving Target

Dan M. Roden, MD

From the Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn.

Correspondence to Dan M. Roden, MD, Professor of Medicine and Pharmacology, Director, Oates Institute for Experimental Therapeutics, Assistant Vice-Chancellor for Personalized Medicine, Vanderbilt University School of Medicine, 1285 Medical Research Bldg IV, Nashville, TN 37232-0575. E-mail dan.roden@vanderbilt.edu

Key Words: Editorials • drugs • ion channels • electrophysiology

An extract of the first 250 words of the full text is provided, because this article has no abstract.

	Introduction

 
Clinicians are well aware that responses to QT-prolonging drugs vary among individuals.¹ A drug dose (and concentration) that produces minimal QT prolongation in one patient may, in an apparently indistinguishable subject, produce marked QT prolongation and torsade de pointes. This variability in response to an exogenous stressor is paralleled by variability in the extent to which a given mutation in the congenital long-QT syndrome prolongs QT interval and causes arrhythmias.² Indeed, it is depressingly common to identify an affected family after an individual subject has died, only to find many other mutation carriers within the kindred, often with normal QT intervals.

Article p 983

A major mechanism contributing to repolarization in the human ventricle is time-dependent outward (repolarizing) potassium current, initially termed I_K.³ Studies beginning in the late 1980s showed that this current includes multiple components, most notably I_Kr and I_Ks.^4,5 Loss-of-function mutations in the genes underlying either of these 2 currents are a major cause of the congenital long-QT syndrome, and I_Kr inhibition is the major mechanism for QT prolongation by virtually all available drugs.¹ Action potential control is much more complex than simply variability in these 2 currents: Multiple other currents flow across the myocyte membrane during an action potential. This more complex view of repolarization presents an opportunity for translational scientists interested in the problem of variability in response to drug challenge or to disease-associated mutations; in particular, it suggests the hypothesis that individuals may vary in response to challenge such as I_Kr block (or . . . [Full Text of this Article]

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