THERAPUTIC TRIAL IN PATIENTS WITH LQTS 3 GENE MUTATION

长QT综合征（LQTS）是一种遗传性疾病，在美国约有1万人，与复极延迟（在ECG上产生QTc间期）、阵发性室性心律失常、晕厥和猝死相关。 最近，已经鉴定了四种遗传形式的LQTS，包括LQT 3，一种钠通道基因突变（SCN 5A，deltaKPQ缺失），其损害钠通道失活。 这项LQT 3患者研究的主要目的是确定：1）低剂量口服钠通道阻滞剂美西律是否显著缩短QTc ≥ 40 msec; 2）美西律长期给药是否与持续QTc缩短和心肌梗死性心脏事件减少相关。该研究包括两个相关部分：1）一项短期（7周）、随机、双盲、安慰剂对照、交叉、剂量范围研究，口服美西律，以确定低剂量美西律是否（标准剂量的1/4或1/2）在显著缩短QTc间期方面与标准剂量的美西律一样有效;（2）长期（38个月）、随机化、双盲、安慰剂对照、交叉，使用第1部分确定的最低有效美西律剂量的安全性和有效性研究，以确定该剂量的美西律长期给药是否与QTc间期持续缩短和无或减少的心律失常相关。与安慰剂治疗相比的心脏事件。 i研究的两个部分将入组40例具有基因定义的突变型钠通道deltaKPQ缺失的LQT 3患者。本研究将在三个临床中心（罗切斯特，纽约;苏城，爱荷华州;和帕维亚，意大利）进行，协调、数据管理和分析中心位于罗切斯特。 患者的临床随访将包括定期数字12导联和高分辨率ECG，用于定量QTc测量。 为了最大限度地提高检测主要和次要终点显著差异的把握度，交叉设计将允许每例患者在分析中作为自己的对照。这项试验应该为遗传性通道病的分子基础抗肿瘤治疗提供新的见解。 这项工作的意义涉及到未来使用分子疗法治疗与先天性和获得性心脏复极障碍相关的离子通道障碍。

The Long QT Syndrome (LQTS), an hereditary disorder involving about 10,000 persons in the U.S., is associated with delayed repolarization (yields QTc interval on ECG), paroxysmal ventricular arrhythmias, syncope, and sudden death. Recently, four genetic forms of LQTS have been identified including LQT3, a sodium-channel gene mutation (SCN5A, deltaKPQ deletion) with impairment of sodium-channel inactivation. The primary aims of this study of LQT3 patients are to determine: 1) if a low dose of the oral sodium-channel blocking drug mexiletine significantly shortens QTc by greater than or equal to 40 msec; and 2) if chronic administration of mexiletine is associated with sustained QTc shortening and a reduction in arrhythmic cardiac events. The study consists of two related parts: 1) a short-term (7-week), randomized, double-blind, placebo-controlled, crossover, dose-ranging study with oral mexiletine to determine if a low dose of mexiletine (1/4 or 1/2 of the standard dose) is as effective as a standard dose of mexiletine in significantly shortening the QTc interval; and 2) a long-term (38-month), randomized, double-blind, placebo-controlled, crossover, safety and efficacy study using the lowest effective mexiletine dose identified in part 1 to determine if chronic administration of this dose of mexiletine is associated with sustained shortening of the QTc interval and absence or a reduction of arrhythmic cardiac events when compared to placebo therapy. Forty LQT3 patients with genetically defined deltaKPQ deletion of the mutant sodium channel will be enrolled in the two parts of the i study. The study will be conducted in three clinical centers (Rochester, NY; Sioux City, IA; and Pavia, Italy) with the coordination, data management, and analysis center in Rochester. Clinical follow-up of the patients will include periodic digital 12-lead and high-resolution ECGs for quantitative QTc measurements. To maximize the power to detect significant differences in the primary and secondary end points, the crossover design will allow each patient to serve as his/her own control in the analysis. The trial should provide new insight into molecular-based, antiarrhythmic therapy for an inherited channelopathy. The significance of this work relates to the future use of molecular therapeutics to treat ion-channel disorders associated with congenital and acquired cardiac repolarization disorders.