Key result
Chloroquine effectively inhibited SQT3 mutant Kir2.1 channels with an IC50 of 3.30 microM, which was not significantly different from wild-type channels (IC50 2.45 microM, P>0.05).
Absolute Event Rate: 3.3% vs 2.45%
p-value: p=>0.05
Chloroquine effectively inhibits SQT3 mutant Kir2.1 channels in vitro, suggesting potential therapeutic utility for variant 3 short QT syndrome.
Hypothesis-generating for SQT3 therapy; should not change practice without in vivo and clinical validation.
Recently identified genetic forms of short QT syndrome (SQTS) are associated with an increased risk of arrhythmia and sudden death. The SQT3 variant is associated with an amino-acid substitution (D172N) in the KCNJ2-encoded Kir2.1 K+ channel. In this study, whole-cell action potential (AP) clamp recording from transiently transfected Chinese Hamster Ovary cells at 37 degrees C showed marked augmentation of outward Kir2.1 current through D172N channels, associated with right-ward voltage-shifts of peak repolarizing current during both ventricular and atrial AP commands. Peak outward current elicited by ventricular AP commands was inhibited by chloroquine with an IC50 of 2.45 microM for wild-type (WT) Kir2.1, of 3.30 microM for D172N-Kir2.1 alone and of 3.11 microM for co-expressed WT and D172N (P>0.05 for all). These findings establish chloroquine as an effective inhibitor of SQT3 mutant Kir2.1 channels.
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Harchi et al. (2009) studied Variant 3 short QT syndrome (SQT3). Chloroquine vs. Wild-type (WT) Kir2.1 channels was evaluated on Inhibition of peak outward current (IC50) (p=>0.05). Chloroquine effectively inhibited SQT3 mutant Kir2.1 channels with an IC50 of 3.30 microM, which was not significantly different from wild-type channels (IC50 2.45 microM, P>0.05).
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