BACKGROUND: Anesthesia in patients with long QT syndrome (LQTS) is a matter of 
concern. Congenital LQTS is most frequently caused by mutations in KCNQ1 
(Kv7.1), whereas drug-induced LQTS is a consequence of HERG (human 
ether-a-go-go-related gene) channel inhibition. The aim of this study was to 
investigate whether the LQT1 mutation A344V in the S6 region of KCNQ1, at a 
position corresponding to the local anesthetic binding site in HERG, may render 
drug insensitive KCNQ1 channels into a toxicologically relevant target of these 
pharmacologic agents. This may suggest that LQTS constitutes not only a 
nonspecific but also a specific pharmacogenetic risk factor for anesthesia.
METHODS: The authors examined electrophysiologic and pharmacologic properties of 
wild-type and mutant KCNQ1 channels. The effects of bupivacaine, ropivacaine, 
and mepivacaine were investigated using two-electrode voltage clamp and whole 
cell patch clamp recordings.
RESULTS: The mutation A344V induced voltage-dependent inactivation in homomeric 
KCNQ1 channels and shifted the voltage dependence of KCNQ1/KCNE1 channel 
activation by +30 mV. The mutation furthermore increased the sensitivity of 
KCNQ1/KCNE1 channels for bupivacaine 22-fold (KCNQ1wt/KCNE1: IC50 = 2,431 +/- 
582 microM, n = 20; KCNQ1A344V/KCNE1: IC50 = 110 +/- 9 microM, n = 24). 
Pharmacologic effects of the mutant channels were dominant when mutant and 
wild-type channels were coexpressed. Simulation of cardiac action potentials 
with the Luo-Rudy model yielded a prolongation of the cardiac action potential 
duration and induction of early afterdepolarizations by the mutation A344V that 
were aggravated by local anesthetic intoxication.
CONCLUSIONS: The results indicate that certain forms of the LQTS may constitute 
a specific pharmacogenetic risk factor for regional anesthesia.