Back to Search
Start Over
Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block.
- Source :
-
PloS one [PLoS One] 2016 Dec 30; Vol. 11 (12), pp. e0163619. Date of Electronic Publication: 2016 Dec 30 (Print Publication: 2016). - Publication Year :
- 2016
-
Abstract
- Background: Drugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Thus, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the "CiPA" initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans.<br />Methods and Results: In this study we assess the ability of eight ECG morphology biomarkers to detect late sodium current block in the presence of QTc prolongation by analyzing a clinical trial where a selective hERG potassium channel blocker (dofetilide) was administered alone and then in combination with two late sodium current blockers (lidocaine and mexiletine). We demonstrate that late sodium current block has the greatest effect on the heart-rate corrected J-Tpeak interval (J-Tpeakc), followed by QTc and then T-wave flatness. Furthermore, J-Tpeakc is the only biomarker that improves detection of the presence of late sodium current block compared to using QTc alone (AUC: 0.83 vs. 0.72 respectively, p<0.001).<br />Conclusions: Analysis of the J-Tpeakc interval can differentiate drug-induced multichannel block involving the late sodium current from selective hERG potassium channel block. Future methodologies assessing drug effects on cardiac ion channel currents on the ECG should use J-Tpeakc to detect the presence of late sodium current block.<br />Trial Registration: NCT02308748 and NCT01873950.<br />Competing Interests: PT Sager has consulting agreements with Biomedical Systems, Charles River, and iCardiac. The other authors report no conflicts. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
- Subjects :
- Adult
Calcium Channel Blockers pharmacology
Cross-Over Studies
Electrocardiography methods
Ether-A-Go-Go Potassium Channels metabolism
Female
Heart Rate drug effects
Humans
Lidocaine pharmacology
Long QT Syndrome metabolism
Male
Mexiletine pharmacology
Phenethylamines pharmacology
Potassium Channel Blockers pharmacology
Sulfonamides pharmacology
Torsades de Pointes metabolism
Verapamil pharmacology
Biomarkers metabolism
Heart drug effects
Sodium metabolism
Sodium Channel Blockers pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 11
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 28036334
- Full Text :
- https://doi.org/10.1371/journal.pone.0163619