Session S93.2

Short-Term QT Variability: A Marker for Reduced Repolarization Reserve in Anthracyclin Therapy

HJ Ritsema van Eck*, FJ Broeyer, G van Herpen, J Burggraaf, JA Kors

Erasmus University
Rotterdam, Netherlands

Prolongation of the QT interval in the electrocardiogram is considered a risk for the development of arrhythmias, in particular Torsade de Points, and its measurement plays an important role in the assessment of drug safety. The standard methodology prescribes the QT interval to be averaged over a minimum of 3 complexes and to be corrected for heart rate. Beat-to-beat variation is lost in the process. Recently this variation was brought forward as a possible measure of repolarization reserve, independent of the QT interval. We studied both QT-interval duration and beat-to-beat variability in patients treated with the cardiotoxic anthracyclin.
We measured with a high degree of precision the QT interval of each complex in 5-minute standard 12-lead ECG recordings. The end of T-wave is determined using the “fiducial segment averaging” (FSA) technique. FSA uses the beat-to-beat coherence of relatively small segments around the T fiducial point. This segment of each individual complex is cross-correlated with the average segment of the remaining complexes and shifted until maximal correlation is obtained. This continues in an iterative process until no further improvement can be achieved. The individual QT intervals are then used for beat-to-beat QT variability calculation. Recordings were made at rest in the supine position using the Cardio Perfect system (Welch-Allyn CardioControl, Delft, The Netherlands) at a sampling rate of 600/s without filtering. We examined 39 patients treated with anthracyclin-based chemotherapy (Doxorubicin, DXR) for early-stage breast cancer. DXR infusions were administered in 4 courses at least one month apart. Recordings were obtained at baseline and at 4 and 24 hours after DXR infusion.
Mean short-term variability (STVmean) was 1.25 ms (1.08-1.42) at baseline of the first course and increased to 1.78 ms (1.48-2.08) and 1.81 ms (1.48-2.13) at 4 and 24 hours after DXR infusion, respectively. During the last course even larger increases were observed, from 1.72 ms (1.38-2.06) at baseline, to 2.45 ms (1.69-3.22) and 3.17 ms (2.35-3.99) at 4 and 24 hours post-administration, respectively. The QT variability index as proposed by Berger showed comparable changes. The QTc (Framingham linear correction) increased by 9.56 ms at 4 hours (P<0.001) and by 11.48 ms (P<0.0001) at 24 hours. There were no serious arrhythmias observed during the trial period.
We showed that after DXR infusion QT-variability increased, which suggests an effect of DXR on the repolarization reserve in humans. The absence of serious arrhythmias can be explained by the relative modest dosing and concomitant moderate increase in STV and QTc. It remains to be elucidated whether these effects relate to an increased susceptibility to anthracyclin-induced heart failure.

(Abstract Control Number: 11)