Abstract
The drug-induced long QT syndrome is a distinct clinical entity that has evolved from an electrophysiologic curiosity to a centerpiece in drug regulation and development. This evolution reflects an increasing recognition that a rare adverse drug effect can profoundly upset the balance between benefit and risk that goes into the prescription of a drug by an individual practitioner as well as the approval of a new drug entity by a regulatory agency. This review will outline how defining the central mechanism, block of the cardiac delayed-rectifier potassium current IKr, has contributed to defining risk in patients and in populations. Models for studying risk, and understanding the way in which clinical risk factors modulate cardiac repolarization at the molecular level are discussed. Finally, the role of genetic variants in modulating risk is described.
Footnotes
This article is available online at http://pharmrev.aspetjournals.org.
doi:10.1124/pr.110.003723.
1 Abbreviations:
- AF
- atrial fibrillation
- APD
- action potential duration
- AV
- atrioventricular
- BVR
- beat-to-beat variability of repolarization
- CAVB
- complete atrioventricular block
- cLQTS
- congenital syndromes of QT prolongation
- diLQTS
- drug-induced long QT syndrome
- EAD
- early afterdepolarization
- ECG
- electrocardiogram
- LQTS
- long QT syndrome
- M cell
- cell in the midmyocardium
- SCD
- sudden cardiac death
- TdP
- torsades de pointes
- TDR
- transmural dispersion of repolarization.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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