TY - JOUR
T1 - Drug-induced torsades de pointes
T2 - The evolving role of pharmacogenetics
AU - Fitzgerald, Patrick T.
AU - Ackerman, Michael J.
N1 - Funding Information:
The Sudden Death Genomics Laboratory and Dr. Ackerman’s research program is supported by the CJ Foundation for SIDS, the Dr. Scholl Foundation, a Clinical Scientist Development Award from the Doris Duke Charitable Foundation, an Established Investigator Award from the American Heart Association, and the National Institutes of Health (HD42569). Dr. Ackerman is a consultant, has intellectual property, and is on the scientific advisory board member for Genaissance Pharmaceuticals, which released the FAMILION™ genetic test for cardiac ion channel abnormalities. Dr. Ackerman is a consultant for Medtronic for their BioPatterns Research Program; for CV Therapeutics, Inc. for QT issues pertaining to ranolazine; and for Pfizer for pediatric drug trials pertaining to the antipsychotic medication Geodon ©.
PY - 2005/11
Y1 - 2005/11
N2 - Drug-induced torsades de pointes (TdP) is a rare, but potentially lethal, unwanted effect of drugs, including many commonly prescribed noncardiac drugs. Despite its low frequency, drug-induced TdP has generated a great deal of angst among physicians and pharmaceutical companies as well as tragedy, albeit rare, among patients. Although in retrospect many patients who died suddenly as a result of drug-induced TdP had identifiable risk factors, prediction in individual cases remains problematic. Over the past decade, tremendous progress has been made with respect to elucidating the fundamental pathogenic mechanisms that underlie drug-induced TdP. The vast majority of drugs associated with "QT liability" and the potential for drug-induced TdP, including all of the drugs removed from the market because of this side effect, are "HERG (human ether-́-go-go-related gene) blockers." These drugs inhibit the KCNH2-encoded HERG potassium channel, which is one of the critical repolarizing forces involved in the exquisite orchestration of the heart's action potential. Consequently, myocyte repolarization is potentially delayed as evidenced by prolongation of the QT interval, thus providing the substrate for drug-induced TdP. Rare mutations in KCNH2 provide the pathogenic substrate for type 2 congenital long QT syndrome (LQTS), thus placing this cardiac potassium channel squarely in the intersection between congenital LQTS (the "Rosetta stone" of the heritable channelopathies) and acquired LQTS (drug-induced TdP). In addition, common polymorphisms residing in the LQTS-causing channel genes may confer heightened arrhythmogenic susceptibility and contribute to the makings of a vulnerable host. This review focuses on the present strategy of identifying "at-risk compounds" and the potential future strategy involving pharmacogenetics to pinpoint "at-risk hosts" in an effort to curb this rare, unintended, but potentially life-threatening side effect.
AB - Drug-induced torsades de pointes (TdP) is a rare, but potentially lethal, unwanted effect of drugs, including many commonly prescribed noncardiac drugs. Despite its low frequency, drug-induced TdP has generated a great deal of angst among physicians and pharmaceutical companies as well as tragedy, albeit rare, among patients. Although in retrospect many patients who died suddenly as a result of drug-induced TdP had identifiable risk factors, prediction in individual cases remains problematic. Over the past decade, tremendous progress has been made with respect to elucidating the fundamental pathogenic mechanisms that underlie drug-induced TdP. The vast majority of drugs associated with "QT liability" and the potential for drug-induced TdP, including all of the drugs removed from the market because of this side effect, are "HERG (human ether-́-go-go-related gene) blockers." These drugs inhibit the KCNH2-encoded HERG potassium channel, which is one of the critical repolarizing forces involved in the exquisite orchestration of the heart's action potential. Consequently, myocyte repolarization is potentially delayed as evidenced by prolongation of the QT interval, thus providing the substrate for drug-induced TdP. Rare mutations in KCNH2 provide the pathogenic substrate for type 2 congenital long QT syndrome (LQTS), thus placing this cardiac potassium channel squarely in the intersection between congenital LQTS (the "Rosetta stone" of the heritable channelopathies) and acquired LQTS (drug-induced TdP). In addition, common polymorphisms residing in the LQTS-causing channel genes may confer heightened arrhythmogenic susceptibility and contribute to the makings of a vulnerable host. This review focuses on the present strategy of identifying "at-risk compounds" and the potential future strategy involving pharmacogenetics to pinpoint "at-risk hosts" in an effort to curb this rare, unintended, but potentially life-threatening side effect.
KW - HERG potassium channel
KW - Ion channels
KW - Long QT syndrome
KW - Pharmacogenetics
KW - Pharmacogenomics
KW - Polymorphisms
KW - Torsades de pointes
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UR - http://www.scopus.com/inward/citedby.url?scp=27744471093&partnerID=8YFLogxK
U2 - 10.1016/j.hrthm.2005.08.007
DO - 10.1016/j.hrthm.2005.08.007
M3 - Article
C2 - 16253929
AN - SCOPUS:27744471093
SN - 1547-5271
VL - 2
SP - S30-S37
JO - Heart rhythm
JF - Heart rhythm
IS - 11 SUPPL. 2
ER -