BACKGROUND: The genes for the long QT syndrome (LQTS) linked to chromosomes 3 
(LQT3) and 7 (LQT2) were identified as SCN5A, the cardiac Na+ channel gene, and 
as HERG, a K+ channel gene. These findings opened the possibility of attempting 
gene-specific control of ventricular repolarization. We tested the hypothesis 
that the QT interval would shorten more in LQT3 than in LQT2 patients in 
response to mexiletine and also in response to increases in heart rate.
METHODS AND RESULTS: Fifteen LQTS patients were studied. Six LQT3 and 7 LQT2 
patients were treated with mexiletine, and its effects on QT and QTc were 
measured. Mexiletine significantly shortened the QT interval among LQT3 patients 
(QTc from 535 +/- 32 to 445 +/- 31 ms, P < .005) but not among LQT2 patients 
(QTc from 530 +/- 79 to 503 +/- 60 ms, P = NS). LQT3 patients (n = 7) shortened 
their QT interval in response to increases in heart rate much more than LQT2 
patients (n = 4) and also more than 18 healthy control subjects (9.45 +/- 3.3 
versus 3.95 +/- 1.97 and 2.83 +/- 1.33, P < .05; data expressed as percent 
reduction in QT per 100-ms shortening in RR). Among these patients, there is 
also a trend for LQT2 patients to have syncope or cardiac arrest under emotional 
or physical stress and for LQT3 patients to have cardiac events either at rest 
or during sleep.
CONCLUSIONS: This is the first study to demonstrate differential responses of 
LQTS patients to interventions targeted to their specific genetic defect. These 
findings also suggest that LQT3 patients may be more likely to benefit from Na+ 
channel blockers and from cardiac pacing because they would be at higher risk of 
arrhythmia at slow heart rates. Conversely, LQT2 patients may be at higher risk 
to develop syncope under stressful conditions because of the combined 
arrhythmogenic effect of catecholamines with the insufficient adaptation of 
their QT interval when heart rate increases.