Thomas Bork Hardahl

Identifying drug-induced repolarization abnormalities from distinct ECG Patterns in congenital long QT syndrome: a study of sotalol effects on T-wave morphology

AbstractBackground: The electrocardiographic QT interval is used to identify drugs with potential harmful effects on cardiac repolarization in drug trials, but the variability of the measurement can mask drug-induced ECG changes. The use of complementary electrocardiographic indices of abnormal repolarization is therefore warranted. Most drugs associated with risk are inhibitors of the rapidly activating delayed rectifier potassium current (Ikr). This current is also inhibited in the congenital type 2 form of the long QT syndrome (LQT2). It is therefore possible that electrocardiographic LQT2 patterns might be used to identify abnormal repolarization patterns induced by drugs. Objective: To develop distinct T-wave morphology parameters typical of LQT2 and investigate their use as a composite measure for identification of d,l-sotalol (sotalol)-induced changes in T-wave morphology. Methods: Three independent study groups were included: a group of 917 healthy subjects and a group of 30 LQT2 carriers were used for the development of T-wave morphology measures. The computerized measure for T-wave morphology (morphology combination score, MCS) was based on asymmetry, flatness and notching, which are typical ECG patterns in LQT2. Blinded to labels, the new morphology measures were tested in a third group of 39 healthy subjects receiving sotalol. Over 3 days the sotalol group received 0, 160 and 320 mg doses, respectively, and a 12-lead Holter ECG was recorded for 22.5 hours each day. Drug-induced prolongation of the heart rate corrected QT interval (QTcF) was compared with changes in the computerized measure for T-wave morphology. Effect sizes for QTcF and MCS were calculated at the time of maximum plasma concentrations and for maximum change from baseline. Accuracy for separating baseline from sotalol recordings was evaluated by area under the receiver operating characteristic curves (AUCs) using all recordings from the time immediately post-dose to maximum change. Results: MCS separated baseline recordings from sotalol treatment with higher accuracy than QTcF for the 160 mg dose: (AUC) 84% versus 72% and for the 320 mg dose: (AUC) 94% versus 87%, p < 0.001. At maximum serum-plasma concentrations and at maximum individual change from baseline, the effect sizes for QTcF were less than half the effect sizes for MCS, p< 0.001. Effect sizes at peak changes of the mean were up to 3-fold higher for MCS compared with QTcF, p< 0.001. In subjects receiving sotalol, T-wave morphology reached similarity to LQT2, whereas QTcF did not. Conclusion: Distinct ECG patterns in LQT2 carriers effectively quantified repolarization changes induced by sotalol. Further studies are needed to validate whether this measure has general validity for the identification of drug-induced disturbed repolarization.

Reference values of electrocardiogram repolarization variables in a healthy population.

INTRODUCTION Reference values for T-wave morphology analysis and evaluation of the relationship with age, sex, and heart rate are lacking in the literature. In this study, we characterized T-wave morphology in a large sample of healthy individuals. METHOD A total of 1081 healthy subjects (83% men; range, 17-81 years) were included. T-wave morphology variables describing the duration, area, slopes, amplitude, and distribution were calculated using 10-second digital electrocardiogram recordings. Multivariate regression was used to test for dependence of T-wave variables with the subject age, sex, and heart rate. RESULTS Lead V5 (men vs women) T-wave variables were as follows: amplitude, 444 versus 317 muV; area, 48.4 versus 33.2 ms mV; Tpeak-Tend interval, 94 versus 92 milliseconds; maximal descending slope, -5.15 versus -3.69 muV/ms; skewness, -0.24 versus -0.22; and kurtosis, -0.36 versus -0.35. Tpeak-Tend interval, skewness, and kurtosis were independent of age, sex, and heart rate (r(2) < 0.05), whereas Bazett-corrected QT-interval was more dependent (r(2) = 0.40). CONCLUSION A selection of T-wave morphology variables is found to be clinically independent of age, sex, and heart rate, including Tpeak-Tend interval, skewness, and kurtosis.

Classification of the long-QT syndrome based on discriminant analysis of T-wave morphology

The long QT syndrome (LQTS) is a genetic disorder, typically characterized by a prolonged QT interval in the ECG due to abnormal cardiac repolarization. LQTS may lead to syncopal episodes and sudden cardiac death. Various parameters based on T-wave morphology, as well as the QT interval itself have been shown to be useful discriminators, but no single ECG parameter has been sufficient to solve the diagnostic problem. In this study we present a method for discrimination among persons with a normal genotype and those with mutations in the KCNQ1 (KvLQT1 or LQT1) and KCNH2 (HERG or LQT2) genes on the basis of parameters describing T-wave morphology in terms of duration, asymmetry, flatness and amplitude. Discriminant analyses based on 4 or 5 parameters both resulted in perfect discrimination in a learning set of 36 subjects. In both cases cross-validation of the resulting classifiers showed no misclassifications either.

Sertindole causes distinct electrocardiographic T-wave morphology changes

Sertindoles propensity to prolong the QT interval relates to blockade of the KCNH2 (HERG) encoded Ikr potassium channel, but there has been limited detailed data on T-wave morphology changes. Digital 12-lead ECG was recorded at baseline and at steady-state in 37 patients switched to sertindole. ECG was analyzed for quantitative T-wave morphology changes and Fridericia-corrected QT duration (QTcF). Prominent T-wave morphology changes occurred during sertindole treatment and in some cases without concomitant prolongation of the QTcF interval. Four patients developed notched T-waves during sertindole treatment. Mean QTc prolongation was 19 ms. The mean effect size was higher for T-wave morphology combination score (MCS) (ES=1.92; 95% CI: 1.35-2.49) compared to the mean effect size for QTcF (ES=0.88; 95% CI: 0.52-1.24). The use of T-wave morphology analysis may become clinically relevant, particularly if shown to be associated with drug-induced arrhythmia risk.

Quantitative Analysis of T‐wave Morphology Increases Confidence in Drug‐Induced Cardiac Repolarization Abnormalities: Evidence From the Investigational IKr Inhibitor Lu 35–138

This study investigates repolarization changes induced by a new candidate drug to determine whether a composite electrocardiographic (ECG) measure of T‐wave morphology could be used as a reliable marker to support the evidence of abnormal repolarization, which is indicated by QT interval prolongation. Seventy‐nine healthy subjects were included in this parallel study. After a baseline day during which no drug was given, 40 subjects received an IKr‐blocking antipsychotic compound (Lu 35–138) on 7 consecutive days while 39 subjects received placebo. Resting ECGs were recorded and used to determine a combined measure of repolarization morphology (morphology combination score [MCS]), based on asymmetry, flatness, and notching. Replicate measurements were used to determine reliable change and study power for both measures. Lu 35–138 increased the QTc interval with corresponding changes in T‐wave morphology as determined by MCS. For subjects taking Lu 35–138, T‐wave morphology was a more reliable indicator of IKr inhibition than QTcF (χ2 = 20.3, P = .001). At 80% study power for identifying a 5‐millisecond placebo‐adjusted change from baseline for QTcF, the corresponding study power for MCS was 93%. As a covariate to the assessment of QT interval liability, MCS offered important additive information to the effect of Lu 35–138 on cardiac repolarization.

The effect of sertindole on QTD and TPTE

Nielsen J, Andersen MP, Graff C, Kanters JK, Hardahl T, Dybbro J, Struijk JJ, Meyer JM, Toft E. The effect of sertindole on QTD and TPTE.

A robust method for quantification of IKr-related T-wave morphology abnormalities

The QTc interval plays an important role in premarket testing of new drugs, but the intrinsic variability of the measurement is critical. Most arrhythmogenic drugs inhibit the IKr current and cause both QTc prolongation and changes in T-wave morphology. Quantification of T-wave morphology may be useful in drug testing, but no robust method exists for this purpose. We present a method for quantification of IKr-related T-wave morphology changes: T-wave asymmetry, flatness and the presence of notches on the T-wave combined to an overall morphology combination score (MCS). In a population of 30 LQT2-subjects (congenital IKr inhibition) and 1096 healthy subjects, both QTcF and MCS yield clear separation between the groups (p<0.001), sensitivity 90%, specificity 95%.

Classification of the long QT syndrome based on discriminant analysis of T-wave morphology

The long QT syndrome (LQTS) is a genetic disorder, characterized by a long QT interval in the ECG, due to abnormal cardiac repolarization. Apart from the QT interval, various parameters, describing T-wave morphology, have been shown to have diagnostic value, but no single ECG parameter has been sufficient. In this study we present a method for discrimination among normal genotypes and mutations in the KCNQ1 (KvLQT1) and KCNH2 (HERG) genes using parameters describing T-wave morphology in terms of duration, asymmetry, flatness and amplitude. Discriminant analyses based on 3, 4, 5, or 6 parameters all resulted in perfect discrimination in a learning set of 22 subjects with respectively 3, 3, 2, and 3 misclassifications in an evaluation set of 17 subjects. In a combined learning set of all 39 subjects both the 5 and 6 parameter classifiers resulted in a single misclassification

T-wave morphology differences depending on genotype in long QT syndrome

Background Methadone is known to block hERG channels in vitro mimicking the molecular changes in patients with loss of function mutations in hERG. In patients methadone causes prolongation of the QT interval and Torsade de Pointes as known from Long QT syndrome type 2 (LQT2). This congruity between the molecular mechanism and clinical findings makes a population of methadone treated subjects ideal to investigate electrocardiogram (ECG) changes due to partial hERG blockade. The aim was to compare healthy controls with methadone induced T-wave morphology changes and patients with congenital LQT2. Methods The populations consisted of 1,081 self reported healthy subjects, 41 genotyped LQT2 patients and 374 heroin addicts enrolled from a methadone maintenance program. A 10 s digital ECGwas obtained from each individual. Dedicated software automated assigned fix-points correlating to essential ECG points of reference including T-wave start, peak and end. This led to computing variables describing T-wave morphologies in five categories: Duration, Area, Amplitude, Slope and Distribution. Results LQT2 and methadone treated patients clearly separates from healthy controls (Table). Furthermore methadone treated patients with T-wave morphologies that increasingly look more and more like LQTS patients as their QT-interval increases compared to methadone users with normal QT-interval e.g.: T amplitude 360 μV for QT< 440 ms and 261 μV for QT>440 ms, (P<0.0001) compared to 201 μV for LQTS2 and 422 μV for healthy subjects. Conclusions The T-wave morphology in subject with prolonged QT interval during methadone treatment resembles the T-wave morphology found in LQT2. T-wave morphology is a promising tool for future screening for drug induced LQTS.