LONG QT SYNDROME PATIENTS WITH MUTATIONS OF THE SCN5A AND HERG GENES HAVE DIFFERENTIAL RESPONSES TO NA-RATE - IMPLICATIONS FOR GENE-SPECIFIC THERAPY( CHANNEL BLOCKADE AND TO INCREASES IN HEART)

Background The genes for the long QT syndrome (LQTS) linked to chromos omes 3 (LQT3) and 7 (LQT2) were identified as SCN5A, the cardiac Na+ c hannel gene, and as HERG, a K+ channel gene. These findings opened the possibility of attempting gene-specific control of ventricular repola rization. We tested the hypothesis that the QT interval would shorten more in LQTS than in LQT2 patients in response to mexiletine and also in response to increases in heart rate. Methods and Results Fifteen LQ TS patients were studied. Six LQT3 and 7 LQT2 patients were treated wi th mexiletine, and its effects on QT and QT(c) were measured. Mexileti ne significantly shortened the QT interval among LQTS patients (QT(c) from 535+/-32 to 445+/-31 ms, P<.005) but not among LQT2 patients (QT( c) 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 tha n 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 a s percent reduction in QT per 100-ms shortening in RR). Among these pa tients, there is also a trend for LQT2 patients to have syncope or car diac arrest under emotional or physical stress and for LQT3 patients t o have cardiac events either at rest or during sleep. Conclusions This is the first study to demonstrate differential responses of LQTS pati ents to interventions targeted to their specific genetic defect. These findings also suggest that LQT3 patients may be more likely to benefi t 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 con ditions because of the combined arrhythmogenic effect of catecholamine s with the insufficient adaptation of their QT interval when heart rat e increases.