Electrocardiogram-based index for the assessment of drug-induced hERG potassium channel block.

INTRODUCTION

Drug-induced block of the hERG potassium channel could predispose to torsade de pointes, depending on occurrence of concomitant blocks of the calcium and/or sodium channels. Since the hERG potassium channel block affects cardiac repolarization, the aim of this study was to propose a new reliable index for non-invasive assessment of drug-induced hERG potassium channel block based on electrocardiographic T-wave features.

METHODS

ERD (early repolarization duration) and T (down-going T-wave slope to T-wave amplitude ratio) features were measured in 22 healthy subjects who received, in different days, doses of dofetilide, ranolazine, verapamil and quinidine (all being hERG potassium channel blockers and the latter three being also blockers of calcium and/or sodium channels) while undergoing continuous electrocardiographic acquisition from which ERD and T were evaluated in fifteen time points during the 24 h following drug administration ("ECG Effects of Ranolazine, Dofetilide, Verapamil, and Quinidine in Healthy Subjects" database by Physionet). A total of 1320 pairs of ERD and T measurements, divided in training (50%) and testing (50%) datasets, were obtained. Drug-induced hERG potassium channel block was modelled by the regression equation B(%) = a·ERD + b·T+ c·ERD·T + d; B(%) values were compared to plasma-based measurements, B(%).

RESULTS

Regression coefficients values, obtained on the training dataset, were: a = -561.0 s, b = -9.7 s, c = 77.2 and d = 138.9. In the testing dataset, correlation coefficient between B(%) and B(%) was 0.67 (p < 10); estimation error was -11.5 ± 16.7%.

CONCLUSION

B(%) is a reliable non-invasive index for the assessment of drug-induced hERG potassium channel block, independently from concomitant blocks of other ions.