Circulation. 2007;116:1137-1144
Published online before print August 13, 2007, doi: 10.1161/CIRCULATIONAHA.107.707877
Published online before print August 13, 2007, doi: 10.1161/CIRCULATIONAHA.107.707877
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(Circulation. 2007;116:1137-1144.)
© 2007 American Heart Association, Inc.
Genetics |
CLINICAL PERSPECTIVE
Long-QT syndrome type 3 (LQT3) is caused by mutations in the sodium channel gene (SCN5A) that increase sodium current and prolong cardiac repolarization. LQT3 patients are more likely to have cardiac arrhythmias at rest and incomplete protection when treated with β-blockers; consequently, LQT3 patients have a more adverse prognosis than most LQTS patients. The sodium channel blocker mexiletine has been proposed as a treatment in LQT3 patients to reduce sodium inward current and to shorten QT interval. Clinical data demonstrate that mexiletine does not abbreviate repolarization in all LQT3 patients; the cause for such a variable response is unknown. We hypothesized that the response to mexiletine could be at least partially inferred from in vitro assessment of the functional profile of the different mutations found in patients. Therefore, we studied in vitro mutations found in patients with variable responses to mexiletine. Our data showed that patients who have a shortened QT interval and a favorable prognosis in response to mexiletine carry mutations that shift the steady-state inactivation curves to negative voltages and cause a higher use-dependent block of mexiletine. On the contrary, patients whose QT intervals are not modified in response to mexiletine carry mutations that do not shift the steady-state inactivation curve or shift it to positive voltages. We propose that if these data are confirmed in a larger and prospective study, it will be reasonable to characterize SCN5A mutations in vitro to predict the response to mexiletine and to tailor treatment for LQT3 patients.
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Footnotes |
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The online Data Supplement, consisting of tables, can be found with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.107.707877/DC1.
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