Comparison of Electrocardiographic Biomarkers for Differentiating Drug-Induced Single vs. Multiple Cardiac Ion Channel Block.
Comparison of Electrocardiographic Biomarkers for Differentiating Drug-Induced Single vs. Multiple Cardiac Ion Channel Block.
复制标题
用于区分药物引起的单一与多重心脏离子通道阻滞的心电图生物标志物的比较。
DOI：
10.1111/cts.12596
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Brockway,BrianP
中科院分区：
文献类型：
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作者：
Brockway,Marina;Mason,JayW;Brockway,BrianP
自2005年国际协调会议引入心律失常原指南以来，没有新的上市药物与Torsade de Pointes不可接受的风险相关。尽管心脏安全性得到了改善，但这些指导方针产生了意想不到的后果，即在早期开发过程中淘汰了可能有益的药物。最近，有研究表明，与仅影响人乙醚- a - go - go相关基因（hERG）相比，如果一种校正的QT （QTc）延长药物影响多个离子通道，那么它可能是安全的，并且这种影响可以通过QT亚间期来区分。我们比较了四种心电图（ECG）复极化指标的预测能力，以区分单通道和多通道阻塞：(i)传统的10秒信号平均重复三次，（ii）使用增加自动测量心跳间隔（btb）密度的三种指标。预测能力采用logistic回归评估，并以受试者工作特征（ROC）曲线下面积（AUC）量化。与传统的10秒信号平均重复次数相比，随着btb测量密度的增加，分类误差的降低幅度在2 - 6之间。
Since introduction of the International Conference on Harmonization proarrhythmia guidelines in 2005, no new marketed drugs have been associated with unacceptable risk of Torsade de Pointes. Although cardiac safety improved, these guidelines had the unintended consequence of eliminating potentially beneficial drugs from pipelines early in development. More recently, it has been shown that a corrected QT (QTc) prolonging drug may be safe if it impacts multiple ion channels vs. only human ether‐a‐go‐go related gene (hERG) and that this effect can be discriminated using QT subintervals. We compared the predictive power of four electrocardiogram (ECG) repolarization metrics to discriminate single vs. multichannel block: (i) traditional 10‐second signal averaged triplicates, and (ii) three metrics that used increasing density of automatically measured beat‐to‐beat (btb) intervals. Predictive power was evaluated using logistic regression and quantified with receiver operating characteristic (ROC) area under the curve (AUC). Compared with the traditional 10‐second signal averaged triplicates, the reduction in classification error ranged from 2−6 with increasing density of btb measurements.