Schwartz P J, Priori S G, Locati E H, Napolitano C, Cantù F, Towbin J A, Keating M T, Hammoude H, Brown A M, Chen L S, Colatsky T J
Cattedra di Cardiologia, Università degli Studi di Pavia, Italy.
Circulation. 1995 Dec 15;92(12):3381-6. doi: 10.1161/01.cir.92.12.3381.
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.
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.
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.
与3号染色体（LQT3）和7号染色体（LQT2）相关的长QT综合征（LQTS）基因被鉴定为心脏钠离子通道基因SCN5A和钾离子通道基因HERG。这些发现开启了尝试对心室复极进行基因特异性调控的可能性。我们检验了以下假设：与LQT2患者相比，美西律以及心率增加时，LQT3患者的QT间期缩短更明显。
对15例LQTS患者进行了研究。6例LQT3患者和7例LQT2患者接受了美西律治疗，并测量了其对QT和QTc的影响。美西律显著缩短了LQT3患者的QT间期（QTc从535±32毫秒缩短至445±31毫秒，P<.005），但未缩短LQT2患者的QT间期（QTc从530±79毫秒缩短至503±60毫秒，P=无统计学意义）。LQT3患者（n=7）因心率增加导致的QT间期缩短幅度远大于LQT2患者（n=4），也大于18名健康对照者（分别为9.45±3.3、3.95±1.97和2.83±1.33，P<.05；数据以RR每缩短100毫秒时QT缩短的百分比表示）。在这些患者中，还有一种趋势，即LQT2患者在情绪或身体应激下更容易发生晕厥或心脏骤停，而LQT3患者在休息或睡眠时更容易发生心脏事件。
这是第一项证明LQTS患者对针对其特定基因缺陷的干预有不同反应的研究。这些发现还表明，LQT3患者可能更有可能从钠离子通道阻滞剂和心脏起搏中获益，因为他们在心率缓慢时发生心律失常的风险更高。相反，LQT2患者在应激状态下可能更容易发生晕厥，因为儿茶酚胺的致心律失常作用与心率增加时QT间期适应不足共同作用。
