Drug-induced long QT syndrome in women: review of current evidence and remaining gaps.
BACKGROUND
Women are at an increased risk of drug-induced long QT syndrome (LQTS). This major cardiac adverse effect may lead to malignant polymorphic ventricular tachycardias, termed torsades de pointes, which may degenerate into ventricular fibrillation and cause sudden death.


OBJECTIVE
This article reviews current evidence and remaining gaps in knowledge about drug-induced LQTS in women.


METHODS
Using the search terms gender, sex, and sex differences in combination with cardiac electrophysiology, long QT syndrome, HERG, membrane transporters, and cytochromes, we conducted a systematic review of the available literature in the PubMed database. Relevant English- and French-language publications (to October 2007) on sex differences in LQTS were identified.


RESULTS
Clinical and experimental studies have reported that gonadal hormones play a role in sex-related differences of QT interval prolongation. Androgens may diminish drug effects on heart repolarization, and estrogens may facilitate arrhythmias. Furthermore, sex-related differences in the density of ion channels may partially explain this phenomenon. However, the magnitude of hormone-dependent differences observed in these studies remains very small compared with the large differences observed in clinical settings. Therefore, many scientists agree that the mechanisms responsible for sex-related differences in the risk of proarrhythmia from drugs remain largely undefined.


CONCLUSIONS
Other factors, such as sex-related modulation of drug disposition in situ, may fill the gaps in our understanding of the sex differences observed in drug-induced LQTS. We suggest that mechanisms such as the modulation of the pharmacokinetics of IKr (rapid component of the delayed rectifier potassium current) blockers, via modulation of intra- and extracellular concentrations, may be of major importance. Sex-specific changes in drug transport and metabolism will result in different plasma and intracellular levels acting along a dose-response effect on IKr block. Consequently, important hormone-dependent factors such as metabolic enzymes and membrane transporters need to be investigated in new basic research studies.
Faculty of Pharmacy, Université de Montréal and Research Center, CHUM, Montreal, Quebec, Canada.
Raymond
R
Hreiche
Pierre
P
Morissette
Jacques
J
Turgeon
D000818:Animals; D015984:Causality; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000453:epidemiology / Q000503:physiopathology; D026901:Membrane Transport Proteins / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000009:adverse effects / Q000493:pharmacokinetics; D012307:Risk Factors; D012727:Sex Characteristics; D017678:Sex Distribution; D012737:Sex Factors; D016171:Torsades de Pointes / Q000139:chemically induced / Q000453:epidemiology / Q000503:physiopathology; D016387:Women's Health
D012739:Gonadal Steroid Hormones; D026901:Membrane Transport Proteins; D026902:Potassium Channel Blockers; D003577:Cytochrome P-450 Enzyme System