Key result
Defining structure-activity relations can reduce drug-induced hERG activity, though hERG is not the sole cause of QT prolongation and QT prolongation is a sub-optimal biomarker for arrhythmia.
This review emphasizes that while evaluating drug effects on hERG channels is crucial for assessing arrhythmia risk, QT prolongation itself is an imperfect biomarker for ventricular fibrillation.
QT prolongation remains an imperfect arrhythmia surrogate; leaves open need for superior biomarkers in drug safety assessment.
This review summarizes current knowledge of the cardiac rapidly activating delayed rectifier potassium current (I(Kr)), and its connection to drug-acquired QT prolongation and the associated risk of ventricular arrhythmia and fibrillation. The molecular characterization of hERG as the structural correlate of I(Kr) and the link between inherited long QT and the KCNH2 gene (hERG), have facilitated mechanistic studies of drug-acquired QT prolongation. The development of high throughput assays to evaluate drug effects on hERG has provided an avenue to determine structure activity relations (SAR) within chemical series. More than 10 years of collective data and structural considerations support the notion that hERG is an unusually promiscuous target among potassium channels, but that defining SAR within a chemical series is a viable strategy to reduce or eliminate hERG activity. Despite a critical need to minimize drug effects on hERG, one should always keep in mind that hERG is not the only structural correlate of QT prolongation, and that QT prolongation is a sub-optimal biomarker for ventricular arrhythmia and fibrillation.
No takes yet. Share an insight, caveat, or question.
Lagrutta et al. (2008) conducted a review in Drug-acquired cardiac arrhythmia and QT prolongation. Drugs affecting the hERG channel was evaluated. Defining structure-activity relations can reduce drug-induced hERG activity, though hERG is not the sole cause of QT prolongation and QT prolongation is a sub-optimal biomarker for arrhythmia.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: