GENETIC SUSCEPTIBILITY IN ACQUIRED LONG QT SYNDROME

许多常用的抗心律失常药物通过阻断心脏钾通道传导延长心室复极和心电图qt间期。在一小部分接受这些药物治疗的患者中，可发生危及生命的多态性室性心动过速，称为点扭转，与QT间期过度延长有关。最近，人们发现这种综合征的先天性形式是由介导电压门控离子通道（包括K+和Na+通道）的基因突变引起的。有相当多的由基因决定的疾病只有在接触药物后才显现出来。因此，先天性长QT综合征中离子通道基因突变的发现提出了一种假设，即一些获得性长QT综合征患者在这些或其他基因中存在亚临床基因突变，但需要药物暴露才能表达表型。本研究将比较使用抗心律失常药物布利特的ALQT先发者一级亲属与非ALQT对照组药物引起的QT间期延长。在ALQT患者亲属中检测到的异常QT反应将为药物性长QT综合征的遗传易感性提供证据，并且将继续进行进一步的研究以试图确定候选基因。本研究的最终目的是确定易感基因型，这将预测在接受qt延长药物治疗的患者中角性扭转的发展。

Many commonly used antiarrhythmic drugs prolong ventricular repolarization and the qt interval on the electrocardiogram by blocking conductance of cardiac potassium channels. In a small percentage of patients receiving these drugs, a life-threatening polymorphic ventricular tachycardia called Torsades de Pointes can occur in association with excessive QT prolongation. Recently, it was found that the congenital form of this syndrome results from mutations in genes which encole voltage-gated ion channels, including K+ and Na+ channels. There is considerable precendent for genetically- determined diseases that become manifested only upon exposure to drugs. Therefore the discovery of ion channel gene mutations in the congenital long QT syndrome raises the hypothesis that some patients in the acquire long QT syndrome harbor subclinical genetic mutations in these or other genes but require drug exposure for expression of the phenotype. This study will compare drug-induced QT prolongation in first degree relatives of ALQT probands to that of non-alqt controls using the antiarrjythmic drug ibutilide. An abnormal QT response detected in the relatives of ALQT patients would provide evidence of a genetic predisposition for drug-induced long QT syndrome, and additional studies would continue in the attempt to identify candidate genes. The ultimate goal of this research is to identify susceptible genotypes which would be predictive of the development of Torsades de Pointes in patients treated with QT-prolonging drugs.