Drug- and non-drug-associated QT interval prolongation
Drug- and non-drug-associated QT interval prolongation
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DOI：
10.1111/j.1365-2125.2010.03660.x
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发表时间：
2010-07-01
影响因子：
3.4
通讯作者：
Stricker, Bruno H. Ch.
中科院分区：
文献类型：
--
作者：
van Noord, Charlotte;Eijgelsheim, Mark;Stricker, Bruno H. Ch.
心源性猝死是发达国家心血管死亡的最常见原因之一。大多数心脏性猝死是由复极紊乱后的急性室性心律失常引起的。复极障碍的一个重要危险因素是使用QT延长药物，可能部分由基因-药物相互作用解释。在这篇综述中，我们将总结QT间期生理学，QT间期延长的已知危险因素，包括药物和药物遗传学的贡献。长QT综合征可以是先天性的，也可以是后天性的。先天性长QT综合征是由离子通道亚单位或调节蛋白编码基因突变引起的，是一种罕见的孟德尔遗传模式的单基因疾病。除此之外，已经确定了与QT间期持续时间相关的几种常见遗传变异。获得性QT间期延长比先天性QT间期延长更普遍。已经确定了几个风险因素，其中使用QT延长药物是最常见的原因。大多数延长QT间期的药物通过阻断hERG编码的钾通道起作用，尽管一些药物主要修饰钠通道。药效学和药代动力学机制均可能导致QT间期延长。药代动力学相互作用通常涉及通过细胞色素P450酶代谢的药物。药效学基因-药物相互作用是由于遗传变异增强了药物的QT延长作用。QT间期延长，通常是由于使用QT间期延长药物，是一个主要的公共卫生问题。最近，已经确定了与QT间期延长相关的常见遗传变异。很少有药物遗传学研究已经进行，以建立获得性QT间期延长的遗传背景，但在这个新发展的领域的其他研究是必要的。
Sudden cardiac death is among the most common causes of cardiovascular death in developed countries. The majority of sudden cardiac deaths are caused by acute ventricular arrhythmia following repolarization disturbances. An important risk factor for repolarization disturbances is use of QT prolonging drugs, probably partly explained by gene-drug interactions. In this review, we will summarize QT interval physiology, known risk factors for QT prolongation, including drugs and the contribution of pharmacogenetics. The long QT syndrome can be congenital or acquired. The congenital long QT syndrome is caused by mutations in ion channel subunits or regulatory protein coding genes and is a rare monogenic disorder with a mendelian pattern of inheritance. Apart from that, several common genetic variants that are associated with QT interval duration have been identified. Acquired QT prolongation is more prevalent than the congenital form. Several risk factors have been identified with use of QT prolonging drugs as the most frequent cause. Most drugs that prolong the QT interval act by blocking hERG-encoded potassium channels, although some drugs mainly modify sodium channels. Both pharmacodynamic as well as pharmacokinetic mechanisms may be responsible for QT prolongation. Pharmacokinetic interactions often involve drugs that are metabolized by cytochrome P450 enzymes. Pharmacodynamic gene-drug interactions are due to genetic variants that potentiate the QT prolonging effect of drugs. QT prolongation, often due to use of QT prolonging drugs, is a major public health issue. Recently, common genetic variants associated with QT prolongation have been identified. Few pharmacogenetic studies have been performed to establish the genetic background of acquired QT prolongation but additional studies in this newly developing field are warranted.