Electrocardiographic Identification of Drug‐Induced QT Prolongation: Assessment by Different Recording and Measurement Methods

Sarapa, Nenad; Morganroth, Joel; Couderc, Jean‐Philippe; Francom, Steven F.; Darpö, Börje; Fleishaker, Joseph C.; McEnroe, Janet D.; Chen, William T.; Zaręba, Wojciech; Moss, Arthur J.

doi:10.1111/j.1542-474x.2004.91546.x

Cited by 82 publications

(89 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although there is a circadian pattern of QTc intervals during the daytime hours (e.g., due to postprandial changes), the variability of QTc values when accurately measured and corrected is much smaller than previously reported (13,24,27).…”

Section: Discussionmentioning

confidence: 61%

Subject-specific profiles of QT/RR hysteresis

Malik¹,

Hnatkova²,

Novotný³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

The time lag of the QT interval adaptation to heart rate changes (QT/RR hysteresis) was studied in 40 healthy subjects (18 females; mean age, 30.4 Ϯ 8.1 yr) with 3 separate daytime (Ͼ13 h) 12-lead electrocardiograms (ECG) in each subject. In each recording, 330 individual 10-s ECG segments were measured, including 100 segments preceded by 2 min of heart rate varying greater than Ϯ2 beats/min. Other segments were preceded by a stable heart rate. In segments preceded by variable rate, QT/RR hysteresis was characterized by parameters of the exponential decay models. The intrasubject SDs of values were compared with the intersubject SD of the individual means. The values were also correlated to individually optimized parameters of heart rate correction. Intrasubject SDs of were substantially smaller than the population SD of individual means (0.390 Ϯ 0.197 vs. 0.711, P Ͻ 0.0001). The values were unrelated to the QT/RR correction parameters. When compared with the corrected QT (QTc) for averaged RR intervals in 10-s ECGs and with the averaged RR intervals in 2-min history, QTc for QT/RR hysteresis led to a substantially smaller SD of QTc values (11.4 Ϯ 2.00, 6.33 Ϯ 1.31, and 4.66 Ϯ 0.85 ms, respectively, P Ͻ 0.0001). Thus the speed with which the QT interval adapts to heart rate changes is highly individual with intrasubject stability and intersubject variability. QT/RR hysteresis is independent of the static QT/RR relationship and should be considered as a separate physiological process. The combination of individual heart rate correction with individual hysteresis correction of the QT interval is likely to lead to substantial improvements of cardiac repolarization studies.QT adaptation; individual QT correction; electrocardiogram measurement; corrected QT variability HEART RATE DEPENDENCY of the electrocardiographic QT interval has been the subject of numerous studies. Electrocardiographic data sets of variable sizes, sources, and quality have been used to investigate the relationship of the QT interval to heart rate (3,12,14,26,28), most frequently with the aim of finding a universally applicable heart rate correction formula. On the contrary, the adaptation of QT interval duration to rapid rate changes, which is the lag with which QT interval duration responds to heart rate changes, has been studied much less frequently. Indeed, in numerous studies that investigated the relationship between QT interval and heart rate in short-term (such as 10 s) electrocardiograms (ECG), the QT adaptation to heart rate changes has been, as a rule, impossible since no heart rate history preceding the measured ECGs was available.The time scale of the adaptation of QT interval to heart rate changes, most frequently termed the QT/RR hysteresis, has been previously approximated in investigations with constant pacing rates. Such experiments measured both the action potential durations (11) and QT intervals in surface ECGs (17). Studies of QT/RR hysteresis in long-term ECG recordings without pacing provocation appeared only recently, ma...

show abstract

Section: Discussionmentioning

confidence: 61%

Subject-specific profiles of QT/RR hysteresis

Malik¹,

Hnatkova²,

Novotný³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…Healthy young adult subjects were enrolled in a previously reported study [5] exploring electrocardiographic identification of drug-induced QT prolongation following treatment with rac-sotalol. The study was open-label, non-randomized with a fixed treatment sequence on 3 consecutive days: a separate baseline day (day 0), a single oral 160 mg dose of rac-sotalol (Betapace®,Berlex Laboratories) on day 1 and a single 320 mg dose of rac-sotalol on day 2.…”

Section: Study Outlinementioning

confidence: 99%

“…Premenopausal women have on average a 10 to 20 ms longer QTc interval than men [3][4][5] and it is well described that women are at higher risk for the development of pro-arrhythmias caused by drugs with an effect on cardiac repolarization, i.e. drugs that further prolong the QTc interval [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QT_cmodelling in a phase 1 study with oral rac-sotalol

Darpö

Karnad

Badilini³

et al. 2014

Br J Clin Pharmacol

Self Cite

View full text Add to dashboard Cite

AIMTo study the differences in QTc interval on ECG in response to a single oral dose of rac-sotalol in men and women. METHODSContinuous 12-lead ECGs were recorded in 28 men and 11 women on a separate baseline day and following a single oral dose of 160 mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000 Hz and analyzed manually in a central ECG laboratory on the superimposed median beat. Concentration-QTc analyses were performed using a linear mixed effects model. RESULTSRac-sotalol produced a significant reduction in heart rate in men and in women. An individual correction method (QTcI) most effectively removed the heart rate dependency of the QTc interval. Mean QTcI was 10 to 15 ms longer in women at all time points on the baseline day. Rac-sotalol significantly prolonged QTcI in both genders. The largest mean change in QTcI (ΔQTcI) was greater in females (68 ms (95% confidence interval (CI) 59, 76 ms) vs. 27 ms (95% CI 22, 32 ms) in males). Peak rac-sotalol plasma concentration was higher in women than in men (mean Cmax 1.8 μg ml −1 (range 1.1-2.8) vs. 1.4 μg ml −1 (range 0.9-1.9), P = 0.0009). The slope of the concentration-ΔQTcI relationship was steeper in women (30 ms per μg ml −1 vs. 23 ms per μg ml −1 in men; P = 0.0135). CONCLUSIONSThe study provides evidence for a greater intrinsic sensitivity to rac-sotalol in women than in men for drug-induced delay in cardiac repolarization. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Women have a longer QTc interval and an increased risk for pro-arrhythmias caused by drug-induced delayed cardiac repolarization.• This increased risk cannot be explained by gender differences in plasma concentration of the drug.• This study evaluated the QTc-plasma concentration relationship after dosing of rac-sotalol in men and women. WHAT THIS STUDY ADDS• When given a therapeutic dose of rac-sotalol, the slope of the relationship between rac-sotalol concentration and change in QTc interval was steeper in women.• This indicates a greater sensitivity in women as compared with men for rac-sotalol-induced QT prolongation, which may contribute to the greater pro-arrhythmic risk in women.

show abstract

“…snapshots of the definitive 12-lead ECGs provide an insight into continuous assessment of arrhythmias (Sarapa et al, 2004).…”

Section: Drug Trials and Safety (Qt And Arrhythmia Evaluation)mentioning

confidence: 99%

2017 ISHNE-HRS expert consensus statement on ambulatory ECG and external cardiac monitoring/telemetry

Steinberg

Varma

Cygankiewicz

et al. 2017

Ann Noninvasive Electrocardiol

Self Cite

103

View full text Add to dashboard Cite

Electrocardiographic Identification of Drug‐Induced QT Prolongation: Assessment by Different Recording and Measurement Methods

Cited by 82 publications

References 22 publications

Subject-specific profiles of QT/RR hysteresis

Subject-specific profiles of QT/RR hysteresis

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QT_cmodelling in a phase 1 study with oral rac-sotalol

2017 ISHNE-HRS expert consensus statement on ambulatory ECG and external cardiac monitoring/telemetry

Contact Info

Product

Resources

About

Electrocardiographic Identification of Drug‐Induced QT Prolongation: Assessment by Different Recording and Measurement Methods

Cited by 82 publications

References 22 publications

Subject-specific profiles of QT/RR hysteresis

Subject-specific profiles of QT/RR hysteresis

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTcmodelling in a phase 1 study with oral rac-sotalol

2017 ISHNE-HRS expert consensus statement on ambulatory ECG and external cardiac monitoring/telemetry

Contact Info

Product

Resources

About

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QT_cmodelling in a phase 1 study with oral rac-sotalol