Accurately measured and properly heart-rate corrected QTc intervals show little daytime variability

Circadian QTc changes have been reported, with conflicting results. Spontaneous QTc variability is important for pharmaceutical cardiac safety studies.

The purpose of this study was to investigate QTc variability in accurately measured and heart-rate corrected daytime data of healthy subjects.

Continuous 12-lead ECGs were recorded in 53 healthy volunteers. For each recording, approximately 320 ECG samples of 10 seconds were obtained throughout the daytime period, all preceded by stable heart rates. In each ECG sample, QT interval was measured on superimposed 12 leads by two independent cardiologists and reconciled. Four RR-interval expressions were used: (a) average of the first three RR of the ECG sample, (b) RR average of the 10-second sample, (c) average of RR intervals in a 2-minute history, and (d) RR intervals of an independently established individual QT/RR hysteresis profile. For all RR-interval expressions, QT intervals were corrected using the Fridericia formula and individually optimized curvature correction. QTc variability was measured by intraindividual QTc standard deviations.

With Fridericia correction and the RR expressions (a) to (d), QTc variability obtained was (a) 9.45 +/- 1.70 ms, (b) 7.80 +/- 1.48 ms, (c) 6.37 +/- 1.64 ms, and (d) 5.81 +/- 1.75 ms. With individualized correction, QTc variability was (a) 8.16 +/- 1.71 ms, (b) 6.71 +/- 1.41 ms, (c) 5.22 +/- 1.13 ms, and (d) 4.56 +/- 1.18 ms. All differences (b) vs (a), (c) vs (b), and (d) vs (c) were highly statistically significant (P <10(-12) in all cases).

Previously reported large QTc variability largely results from methodologic imprecision. Little QTc variability is present in daytime recordings of healthy subjects. Consequently, QT-related pharmaceutical cardiac safety studies can be made smaller without decreasing their power.