Priori S G, Cantù F, Schwartz P J
Centro di Fisiologia Clinica e Ipertensione, Università degli Studi di Milano, Italy.
Schweiz Med Wochenschr. 1996 Oct 12;126(41):1727-31.
The idiopathic long QT syndrome is a congenital disease characterized by prolongation of the QT interval and by stress-induced syncopal episodes caused by the development of "torsades de pointes". Over the last decade, the great advances in the field of molecular biology have made it possible to elucidate the genetic causes of the disease. In particular, three genes have been implicated in the pathogenesis of the disease: SCN5A (LQT3), encoding for the cardiac sodium channel and located on chromosome 3, HERG (LQT2), encoding for a cardiac potassium channel (Ikr) and located on chromosome 7 and KVLQT1 (LQT1), located on chromosome 11 and encoding for a cardiac potassium channel whose electrophysiologic profile is still undefined. Within each of these genes several different mutations have been identified and subsequently expressed to determine the electrophysiological changes induced by the mutation in the normal function of the channels. These studies have suggested that LQT3 is caused by alterations in the inactivation of cardiac sodium channels while LQT2 is caused by a reduction in the delayed rectifier potassium current. Based on this evidence, we developed the first cellular model for LQTS in order to provide a mean of assessing the effect of different interventions in two different forms of disease, LQT2 and LQT3. We exposed guinea pig ventricular myocytes to anthopleurin, a toxin that interferes with the inactivation of INa, and to dofetilide, a selective blocker of Ikr, obtaining a prolongation of cellular repolarization with both drugs. We then exposed cells to a Na+ channel blocker, mexiletine, which significantly reduced APD in cells treated with anthopleurin while it did not modify the prolongation induced by dofetilide. In addition, anthopleurin-treated cells demonstrated a greater shortening of APD to rapid pacing than both control and dofetilide-treated cells. Based on this experimental evidence, we tested the same therapeutic interventions, mexiletine and pacing, in fifteen genetically characterized LQTS patients. Mexiletine significantly shortened the QT interval in LQT3 patients but not in LQT2 patients. When we examined the response to an increase in heart rate, we found that LQT3 patients had a more shortened QT interval in response to heart rate changes than LQT2 patients and than healthy controls.
特发性长QT综合征是一种先天性疾病，其特征为QT间期延长以及由“尖端扭转型室性心动过速”发作所导致的应激性晕厥。在过去十年中，分子生物学领域的重大进展使得阐明该疾病的遗传病因成为可能。特别是，有三个基因与该疾病的发病机制有关：SCN5A（LQT3），编码心脏钠通道，位于3号染色体上；HERG（LQT2），编码一种心脏钾通道（Ikr），位于7号染色体上；以及KVLQT1（LQT1），位于11号染色体上，编码一种心脏钾通道，其电生理特性仍未明确。在这些基因中的每一个中都已鉴定出几种不同的突变，并随后进行表达，以确定该突变在通道正常功能中所诱导的电生理变化。这些研究表明，LQT3是由心脏钠通道失活的改变引起的，而LQT2是由延迟整流钾电流的减少引起的。基于这一证据，我们开发了首个LQTS细胞模型，以便提供一种手段来评估不同干预措施对两种不同形式疾病LQT2和LQT3的影响。我们将豚鼠心室肌细胞暴露于一种干扰INa失活的毒素——海葵毒素，以及一种Ikr的选择性阻滞剂——多非利特，两种药物均使细胞复极化延长。然后我们将细胞暴露于一种钠通道阻滞剂——美西律，它显著缩短了用海葵毒素处理的细胞的动作电位时程，而对多非利特所诱导的延长没有影响。此外，与对照细胞和多非利特处理的细胞相比，用海葵毒素处理的细胞在快速起搏时动作电位时程的缩短幅度更大。基于这一实验证据，我们在15名经基因特征化的LQTS患者中测试了相同的治疗干预措施——美西律和起搏。美西律显著缩短了LQT3患者的QT间期，但对LQT2患者无效。当我们检查心率增加时的反应时，我们发现LQT3患者在心率变化时QT间期缩短的程度比LQT2患者和健康对照更大。
