Fractionated Repolarization Induced by Sotalol in Healthy Subjects

Over the past five years, regulatory authorities have been increasingly concerned with QT prolongations induced by non-cardiac drug and have recommended pharmaceutical companies to include a careful assessment of the QT interval in their drug development programs. There are controversies around the predictive value of QT prolongation in safety-drug assessment studies. The prolongation of the QT interval is an imperfect, but accepted, surrogate marker of drug cardiac toxicity. In this study, we hypothesize that the inhomogeneous effect of QTprolonging drug in the different layers of the myocardium would not only delay cardiac repolarization, but also perturb the repolarization wavefront on surface ECGs. Principal component analysis (PCA) was applied to the 12-lead ECG Holter recordings. The first two eigenvectors (ev1, ev2) were computed. From PCA, several parameters were calculated based on the first eigenvector and on the T-loop. We demonstrated slower repolarization and perturbed T-wave front; 30 min after sotalol administration, turbulence of repolarization velocity increased by 9.02%, p < 0.05, occurring prior to QT prolongation. These abnormalities were mainly located in the ascending part of the T-wave, whereas the descending part seemed to be less affected at this early phase. In conclusion, analyzing repolarization morphology might help identifying early drug-induced repolarization changes, which could be missed when relying exclusively on QT measurements. 1