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的传导而延长心室复极和心电图上的qt间期。 在接受这些药物的一小部分患者中，可发生与QT间期延长过度相关的称为尖端扭转型室性心动过速的危及生命的多形性室性心动过速。 最近，人们发现这种综合征的先天性形式是由基因突变引起的，这些基因与电压门控离子通道（包括K+和Na+通道）有关。 有相当多的先例表明，基因决定的疾病只有在接触药物后才表现出来. 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这样的假设，即获得性长QT综合征中的一些患者在这些或其他基因中具有亚临床基因突变，但需要药物暴露以表达表型。 本研究将比较使用抗心律失常药物伊布利特的ALQT先证者与非ALQT对照者的一级亲属中药物诱导的QT间期延长。 在ALQT患者亲属中检测到的异常QT反应将为药物诱导的长QT综合征的遗传易感性提供证据，并将继续进行其他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，这些基因型可预测接受QT延长药物治疗的患者发生尖端扭转型室性心动过速。

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.