Early QT Research Articles

Seven day continuous ambulatory electrocardiographic telemetric study with pocket electrocardiographic recording device for detecting hydroxychloroquine induced arrhythmias.

Objective:The use of hydroxychloroquine (HCQ) for COVID-19 treatment and prophylaxis raised issues concerning its cardiac safety owing to the possibility of QT prolongation and arrhythmias. There was no study on long-term electrocardiographic telemetry monitoring of patients taking HCQ. We planned a continuous electrocardiographic Holter telemetry of these patients for 7 days.Material and Methods:Health care workers taking HCQ as pre exposure prophylaxis and patients on HCQ were monitored using seven day Holter electrocardiographic telemetry with continuous beat to beat analysis. Telemetry can instantly convey any arrhythmic event or significant QT prolongation to the medical faculty.Results:Twenty-five participants with a mean age of 42.4 ± 14.1 years were included in the study; 40% were females. Twenty percent of participants needed to stop HCQ. Four patients developed QT prolongation >500 ms and needed to stop HCQ, one patient had accelerated idioventricular rhythm and stopped treatment, and one had short episodes of atrial fibrillation. No malignant arrhythmia or ventricular arrhythmia, or torsade de pointis were noted. No episode of significant conduction disturbance and arrhythmic death was noted. Baseline mean QTc was 423.96 ± 32.18 ms, mean QTc corrected at 24 h was 438.93 ± 37.95, mean QTc was 451.879 ± 37.99 at 48 h, and change in baseline mean QTc to max QTc was 30.74 ± 21.75 ms at 48 h. All those who developed QTc prolongation >500 ms were greater than 50 years of age.Conclusion:Ambulatory telemetry ECG monitoring detects early QT prolongation, and stopping drugs prevents malignant arrhythmias. HCQ seems to have less risk of QT prolongation in young, healthy individuals.

Would field potential duration, recorded from human induced pluripotent stem cell-derived cardiomyocytes, have utility as an early QT screen?

Would field potential duration, recorded from human induced pluripotent stem cell-derived cardiomyocytes, have utility as an early QT screen?

Clinical ECG Assessment.

With the adoption of the ICH E14 guidance, the thorough QT/QTc (TQT) study has become the focus of clinical assessment of an NCE's effects on ECG parameters. The TQT study is used as a guide to the liability of a drug to cause proarrhythmias on the basis of delayed cardiac repolarization. Around 300 TQT studies have been performed since 2005 and through interactions between sponsors and regulators, especially FDA's Interdisciplinary Review Team (IRT) for QT studies. These studies can today be performed more effectively and with great confidence in the generated data. This chapter will discuss technical features and the design and analysis of TQT studies, how assay sensitivity is demonstrated, and examples from recently conducted studies. ECG assessment for drugs that cannot be safely given to healthy volunteers is also addressed, and examples from studies in cancer patients and in healthy volunteers with tyrosine kinase inhibitors are discussed. The TQT study is resource intensive and designed to solely evaluate whether an NCE prolongs the QTc interval. If data with similar confidence can be generated from other studies that are routinely performed as part of the clinical development, this would represent a more optimal use of human resources. Methods and approaches to increase the confidence in ECG data derived from "early QT assessment" in single-ascending/multiple-ascending dose studies are therefore discussed, and a path toward replacing the TQT study using these approaches will be outlined.

Early QT assessment--how can our confidence in the data be improved?

Exposure-response (ER) analysis has emerged as an important tool to interpret QT data from thorough QT (TQT) studies and allows the prediction of effects in the targeted patient population. Recently, ER analysis has also been applied to data from early clinical pharmacology studies, such as single and multiple ascending dose studies, in which high plasma concentrations are often achieved. In line with this, there is an on-going discussion between sponsors, academicians and regulators on whether 'early QT assessment' can provide sufficiently high confidence in assessment of QT prolongation to replace the TQT study. In this article, we discuss how QT assessment can be applied to early clinical studies ('early QT assessment') and what we believe is needed to achieve the same high confidence in the data as we currently obtain from data from the TQT study. The power to exclude a QTc effect exceeding 10 ms in small sample sizes using ER analysis will be discussed and compared with time-matched analysis, as described in the ICH E14 guidance. Two examples of early QT assessment are shared; one negative and one positive, and the challenge in terms of demonstrating assay sensitivity in the absence of a pharmacological positive control will be discussed. Finally, we describe a recent research proposal, which may generate data to support the replacement of the TQT study with data from QT assessment in early phase 1 studies.

An in silico canine cardiac midmyocardial action potential duration model as a tool for early drug safety assessment

Cell lines expressing ion channels (IC) and the advent of plate-based electrophysiology device have enabled a molecular understanding of the action potential (AP) as a means of early QT assessment. We sought to develop an in silico AP (isAP) model that provides an assessment of the effect of a compound on the myocyte AP duration (APD) using concentration-effect curve data from a panel of five ICs (hNav1.5, hCav1.2, hKv4.3/hKChIP2.2, hKv7.1/hminK, hKv11.1). A test set of 53 compounds was selected to cover a range of selective and mixed IC modulators that were tested for their effects on optically measured APD. A threshold of >10% change in APD at 90% repolarization (APD(90)) was used to signify an effect at the top test concentration. To capture the variations observed in left ventricular midmyocardial myocyte APD data from 19 different dogs, the isAP model was calibrated to produce an ensemble of 19 model variants that could capture the shape and form of the APs and also quantitatively replicate dofetilide- and diltiazem-induced APD(90) changes. Provided with IC panel data only, the isAP model was then used, blinded, to predict APD(90) changes greater than 10%. At a simulated concentration of 30 μM and based on a criterion that six of the variants had to agree, isAP prediction was scored as showing greater than 80% predictivity of compound activity. Thus, early in drug discovery, the isAP model allows integrating separate IC data and is amenable to the throughput required for use as a virtual screen.

Heartbeat dynamics in adrenergic blocker treated conscious beagle dogs

Introduction Adrenergic blockade as a treatment for chronic heart failure (CHF) has proved effective, but its pharmacological mechanism on CHF remains unclear. In the past two decades, studies on heart rate variability (HRV) have reported that CHF patients generally have a reduced temporal complexity in heart rate variability. On the other hand, adrenergic blockers have been shown to restore such complexity. Fractal analysis is a novel and efficient tool to explore the adrenergic blockade effect on HRV. This paper applies the detrended fluctuation analysis (DFA) and multifractal DFA (MF-DFA) methods in an attempt to understand the effect of adrenergic blockade on cardiac dynamics in conscious beagle dogs. Methods DFA and MF-DFA analysis are conducted on RR interval data generated from telemetry instrumented dogs receiving a combination of 15 mg/kg nadolol and 5 mg/kg phenoxybenzamine orally administered at the 22nd and 34th hour in a parallel design ( n = 12). All dogs had approximately 48 h of beat-to-beat heart rate measurements recorded in the left ventricle. Complexity measures for heartbeat series are compared between the blocker and vehicle group. We also compute traditional statistics for HRV and spectral parameters and examine their correlation with fractal analysis. Results When compared to the vehicle group, the adrenergic blocker group had: 1) longer RR intervals ( p = 0.02) and lower beat-to-beat variability ( p = 0.04); 2) decreased low frequency (LF) and high frequency (HF) power ( p = 0.03), and higher LF-to-HF ratio; 3) larger middle-range scaling exponents ( p < 0.01); 4) broader multifractal spectra ( p = 0.03) with higher dominant singularity indices ( p = 0.02). Discussion Our results show that 1) adrenergic blockade alters the sympathovagal balance; 2) adrenergic blockers enhance the complexity of the cardiac dynamics; 3) the adrenergic blockade effect on cardiac dynamics is primarily the attenuation of small fluctuations in RR intervals. Fractal analysis also has the potential to be applied to early QT diagnosis.

Rate adaptation of QT intervals during and after exercise in children with congenital long QT syndrome.

To improve the diagnostic criteria of the congenital long QT syndrome in borderline cases we examined rate adaptation of ventricular repolarization phases during exercise and subsequent recovery in children with the long QT syndrome and controls. Nineteen children with definite long QT syndrome and 19 healthy controls underwent exercise testing. QT intervals were measured to the apex (early QT), to the end (total QT) and from apex to the end of the T wave (late QT) at heart rates from 90 by steps of 10 to 150 beats, min-1. In 11/19 long QT syndrome patients (61%) and 2/19 controls (12%) the total QT lengthened during the recovery phase compared with exercise (P = 0.005) at the lowest comparable heart rate. No difference was found between the groups during exercise. The sensitivity of rate adaptation of repolarization intervals was analysed by calculating linear regression slopes relating the QT intervals to the heart rates. During recovery, slopes relating the total QT to heart rate were steeper in long QT syndrome patients than those in controls (-2.50 +/- 0.82 vs -1.79 +/- 0.47, P = 0.003). Total QT/heart rate slopes differed between exercise and recovery phases in the long QT syndrome group only (-1.77 +/- 0.71 vs 2.50 +/- 0.82, P = 0.009). In long QT syndrome patients, the difference in total QT/heart rate slopes was mainly because the late QT/heart rate slopes indicating inhomogeneity of repolarization were steeper during recovery (-1.27 +/- 0.74) than during exercise (-0.46 +/- 0.29, P < 0.0001). After exercise in long QT syndrome children the QT interval lengthens abnormally and inhomogeneity of repolarization increases. Evaluation of the QT interval, and especially its late portion after exercise, may help in establishing the diagnosis of long QT syndrome.

Dynamics of the QT interval during and after exercise in healthy children.

The dynamics and homogeneity of the QT interval have been used as indicators of susceptibility to ventricular arrhythmias. We determined the relationship between QT intervals and heart rate during exercise testing and subsequent recovery in 18 healthy children. The QT intervals were measured to the apex (early QT), to the end (total QT), and from the apex to the end of the T wave (late QT) (inhomogeneity of repolarization) at heart rates from 60 by steps of 10 to 180 beats.min-1. Group mean total QT and early QT exhibited better linear correlations with heart rate (r 0.998 and 0.999) than with cardiac cycle length (r 0.954 and 0.959). The slope relating total QT to heart rate was -1.30 during exercise and -1.42 during recovery (P < 0.05). The corresponding slopes relating early QT to heart rate were -1.11 and -1.30 (P < 0.05). Late QT, as a proportion of total QT, increased at high heart rates. Rate correction using Bazett's method gave abnormal total QT values (> 440 ms) in 12 children (67%) whereas linear correction gave values below 440 ms only. In conclusion, the relationship between QT and heart rate is linear and differs during exercise and recovery. Inhomogeneity of repolarization increases at high heart rates. Linear correction of total QT and early QT intervals improves the evaluation of repolarization duration in exercise testing in children.

QT dispersion and mortality after myocardial infarction

QT dispersion may serve as a measure of variability in ventricular recovery time and may be a means of identifying patients at risk of arrhythmias and sudden death after acute myocardial infarction. We investigated this possibility on electrocardiograms (ECGs) recorded 2 or 3 days after infarction (early) and at least 4 weeks later (late). 163 patients who died between 1 day and 5 years after infarct were compared with an equal number of survivors matched for age and sex. 53 of the patients who died and 82 survivors also had late ECGs. There was no difference in early QT dispersion between the patients who died and the survivors (mean QT c dispersion 112·1 [SD 44·4] vs 109·9 [42·7] ms 1/2). QT c dispersion fell significantly from early to late ECGs in survivors (110·9 [48·5] to 76·5 [28·8] ms 1/2), but not in patients who died during follow-up (108·0 [51·0] to 98·9 [43·1] ms 1/2). The difference between the groups in the mean change was significant (34·4 [55·2] vs 9·1 [60·8] ms 2, p=0·016). QT dispersion measured on an ECG recorded 2 or 3 days after acute myocardial infarction does not predict mortality during the next 5 years. Increased QT dispersion on ECGs recorded at least 4 weeks after infarct may be associated with subsequent mortality, but this finding must be confirmed in a prospective trial.