Investigating the effect of sotalol on the repolarization intervals in healthy young individuals
ABSTRACT The dissociation between a drug-induced increase of the QT interval prolongation and an increased risk for ventricular arrhythmias has been suggested by academic investigators and regulatory agencies. Yet, there are no alternative or complimentary electrocardiographic (ECG) techniques available for assessing the cardiotoxicity of novel compounds. In this study, we investigated a set of novel ECG parameters quantifying the morphology of the T-loop. In a group of healthy individuals exposed to sotalol, we compared their drug-induced changes to the drug-induced prolongations of the QTc, QTc apex and T-peak to T-end intervals.
We implemented a set of parameters describing the morphology of the T loop in its preferential plane. These parameters measure the time interval needed for the heart vector amplitude to change from its maximum value to a time when its amplitude has been reduced by 30%, 50%, and 70%. These measurements are called early repolarization duration (ERD) when they are located before the T-wave apex and late repolarization duration (LRD) when measured after the apex. They depend on both the speed of the repolarization process and the morphology of the T loop. Thirty-nine healthy individuals were exposed to sotalol in a crossover-design study. Sixteen ECGs were recorded per day during 3 days. The first day (day 0) was baseline; a single dose of sotalol (160 mg) was given during day 1, and a double dose was given during day 2 (320 mg). The plasma concentration of the drug was measured just before the ECG recordings.
The values of all investigated parameters revealed a dose-dependent effect of sotalol (in average between parameters, rho = 0.9, P < .001). Our investigations described profound and statistically significant changes in the morphology of the vectorial T loop for day 1 (peak effect of sotalol: DeltaERD(50%) = 23 +/- 6 msec, P < .05; DeltaLRD(50%) = 8 +/- 3 msec, P = .05) and day 2 (peak effect of sotalol: DeltaERD(50%) = 51 +/- 14 msec, P < .05; DeltaLRD(50%) = 20 +/- 12 msec, P = .05). When investigating the timing of peak drug concentration and peak effect of the drug on the various repolarization parameters, we found asynchrony between ERDs/LRDs (> or = 3.5 hours after dosing) and QTc/QTc apex profiles (< 3.5 hours after dosing), suggesting that the time of maximum prolongation on the repolarization process was not synchronized with the time of maximum drug-induced heterogeneity of repolarization.
This study describes the sotalol-induced changes of the T-loop morphology in healthy individuals based on novel vectocardiographic parameters. These observations might help in improving the next generation of ECG markers for the evaluation of drug cardiotoxicity.
SourceAvailable from: Julia Ramírez-García[Show abstract] [Hide abstract]
ABSTRACT: In predicting the risk of suffering from ventricular arrhythmias, the dynamics of QT and T-peak-to-T-end (Tpe) intervals after changes in heart rate (HR) provide richer information than their values themselves. In this study, QT/RR and Tpe/RR dynamics were investigated. Electrocardiogram (ECG) recordings of healthy subjects were analyzed during a head-up tilt test. ECGs were delineated using multi-lead (ML) and single-lead (SL) techniques and the QT and Tpe intervals series were obtained. QT/RR and Tpe/RR dynamics were modeled using a nonlinear system, from which the time constant of adaptation t90 was derived. QT/RR dynamics is similar using SL or ML delineation, with adaptation times being: tSL90[s] = 49.7 +/-29.0, tML90 [s] = 47.1 +/- 20.1. The Tpe interval responded more abruptly to HR when calculated using SL as compared to ML. Consequently, Tpe/RR dynamics were characterized by different adaptation time constants depending on whether SL or ML was used: tSL90 [s] = 25.6 +/- 37.3, tSL90 [s] = 56.4 +/- 48.3. QT dynamics can be invariantly characterized using either SL or ML delineation, while Tpe dynamics are highly sensitive to the delineation method. Differences arise from the way SL and ML delineation are affected by T-wave loop rotation. Care should be taken when electrophysiological interpretation is provided to measurements obtained from one or the other delineation methods.Computing in Cardiology (CinC), 2012; 01/2012
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ABSTRACT: Background Previous studies investigated the QT/RR relationship by linear regressions of QT and RR intervals. However, the pattern of the QT/RR relationship is not necessarily linear. This study investigated the QT/RR and T-peak-to-end (Tpe)/RR curvatures and corresponding slopes in chronic heart failure (CHF) patients, and studied their differences between sudden cardiac death (SCD) victims and others. Methods Holter ECG recordings of 650 CHF patients were analyzed. RR, QT and Tpe series were obtained and for each patient, the data of each subject were fitted with a non-linear regression function of the form: QT = χ + φ(1-RRγ), where γ is the QT/RR curvature . The same regression formula was applied to the Tpe interval series. The slopes (dimensionless units) were calculated at the averaged RR intervals and at RR of 1 second. Results The median (difference between 75th and 25th percentile) of the curvature parameter was 0.226 (2.39) for QT/RR and -0.002 (3.64) for Tpe/RR in the overall sample. For the QT/RR slope, these values were 0.170 (0.12) and 0.190 (0.10) when evaluated at RR = 1 and at the averaged RR, respectively, while for the Tpe/RR slope the values were 0.016 (0.04) and 0.020 (0.04), respectively. The Tpe/RR slope showed high statistical significance for separation of SCD victims and others, particularly when evaluated at the averaged RR (median values of 0.040 vs 0.020, p = 0.002), but also when evaluated at RR = 1 second (0.026 vs 0.015, p = 0.023). Patients with values of Tpe/RR slope above 0.042 had double incidence of SCD, for the case of the slope being evaluated at RR = 1 second, and triple incidence for the case of the slope being evaluated at the averaged RR. The QT/RR slope and curvature, as well as the Tpe/RR curvature, were not different in SCD victims and in others. Conclusions Non-linear regression models based on curvature and slope characteristics, individually obtained for each patient, were used to characterize the QT/RR and Tpe/RR relationships. Steeper Tpe/RR slopes, obtained after adjusting for the curvature parameter, were associated with higher incidence of SCD. The curvature parameter itself did not show SCD predictive value.Journal of Electrocardiology 11/2014; 47(6). DOI:10.1016/j.jelectrocard.2014.08.013 · 1.36 Impact Factor
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ABSTRACT: Increased QT /RR and Tpe /RR slopes have been shown to be independent predictors of sudden cardiac death (SCD) when analyzed over a 24-hour ECG recording. The circadian influence on the QT /RR slope is well-known but it has never been tested on the Tpe /RR slope. This work studied the inter-individual variability of the curvature and slope of QT /RR and Tpe /RR, as well as their circadian pattern in women and men. Holter ECG recordings of 385 patients with chronic heart failure (CHF) from the " MUSIC " database were analyzed. ECGs were delineated using a single-lead procedure over the first principal component lead derived to emphasize the T-wave. RR, QT and Tpe series were obtained and for each patient, a regression equation was fitted, where γ is the QT /RR or Tpe /RR curvature , and Δ is the slope of the regression pattern evaluated at the medium RR value. The median (IQR) slope was Δ QT = 0.194 (0.11), and Δ Tpe = 0.018 (0.04). The median (IQR) curvature was γ QT = 0.993 (0.17) and γ Tpe = 1.000 (0.04), respectively. The circadian pattern modulated the QT /RR and Tpe /RR curvature and slope, with statistically significant differences between day and night for QT /RR slope. No statistically significant differences in gender were found in this study. According to the results in this work, the time of the day should be considered when using QT /RR slope for SCD risk prediction, but the Tpe /RR slope is less sensitive to the circadian pattern.Computing in Cardiology, Cambridge, MA; 09/2014