214 Gene-specific effect of beta-adrenergic blockade on QT duration in the Long QT syndrome

BackgroundIn the long QT syndrome (LQTS) the clinical efficacy of beta-blocker treatment differs according to the genotype. We aimed to asses the effect of beta-blocker treatment in LQT1 and LQT2 patients.Patients and methods24-hour Holter ECG were recorded before and after beta-blocking therapy initiation in genotyped LQT1 (n=30, 8 males, mean age 21±17) and LQT2 patients (n=16, 8 males, mean age 19±15). QT duration was measured on consecutive 1-minute averaged QRS-T complexes leading to up to 1440 QT-RR pairs for each recording. Then, we computed subject- and condition-specific log/log QT/RR relationships which were used to calculate QT interval duration at RR=1000ms (QT1000=1000*).ResultsBefore treatment, coefficients were higher in LQT2 than in LQT1 patients (0.53±0.10 vs. 0.40±0.11, p<0.001) and QT1000 was longer in LQT2 than in LQT1 patients (521±38 vs. 481±39ms, p<0.01).Beta-blockers significantly prolonged the mean RR interval (RR = 827 ± 161 ms before treatment and 939±197ms on beta-blocker, p<0.0001). The coefficients were not significantly modified by beta-blockers (0.41±0.9 in LQT1 patients and 0.52±0.12 LQT2 patients). Beta-blocker treatment was associated with a prolongation of the QT1000 interval (from 481±39 to 498±43ms, p<0.01) in LQT1 patients but with a shortening in LQT2 patients (from 521±38 to 503±32ms, p<0.01).ConclusionsOur results confirm the elevated coefficient of the QT/RR relationship in LQTS patients. LQT2 patients showed higher coefficient and longer QT1000 when compared to LQT1 patients. The effect of beta-adrenergic blockade on QT1000 duration was gene-specific. Given the demonstrated efficacy of beta-blockers in LQT1 and 2 patients, our data suggest that QT1000 might be a poor predictor of outcome under anti-adrenergic therapy

206 The time course of new T-wave ECG descriptors following single and double dose administration of Sotalol in healthy subjects

IntroductionThe aim of the study was to assess the time course effect of IKr blockade on ECG biomarkers of ventricular repolarization and to evaluate the accuracy of a fully automatic approach for QT duration evaluation.Methods12-lead digital ECG Holter were recorded in 38 healthy subjects (27 males, mean age=27.4±8.0 years) on baseline conditions (day 0) and after administration of 160 mg (day 1) and 320 mg (day 2) of d-l Sotalol. For each 24-hour period and each subject, ECGs were extracted every 10 minutes during the 4-hour period following drug dosage. Ventricular repolarization was characterized using 3 biomarker categories: conventional ECG time intervals, Principal Component Analysis (PCA) analysis on the T-wave, and fully automatic biomarkers computed from a mathematical model of the T-wave.ResultsQT interval was significantly prolonged starting 1h20 minutes after drug dosing with 160 mg and 1h 10 minutes after drug dosing with 320 mg. PCA ventricular repolarization parameters sotalol-induced changes were delayed (>3 hours). After sotalol dosing, the early phase of the T-wave changed earlier than the late phase prolongation. Globally, the modeled surrogate QT paralleled manual QT changes.The duration of manual QT and automatic surrogate QT were strongly correlated (R2=0.92, p<0.001). The Bland & Altman plot revealed a non-stationary systematic bias (bias =26.5ms ±1.96*SD = 16ms).ConclusionsChanges in different ECG biomarkers of ventricular repolarization display different kinetics after administration of a potent potassium channel blocker. These differences need to be taken into account when designing ventricular repolarization ECG studies

Time- and rate-dependent alterations of the QT interval precede the onset of torsade de pointes in patients with acquired QT prolongation.

Abstract Objectives. The purpose of this study was to determine whether the QT interval dynamics that precede torsade de pointes are consistent with the initiation of this arrhythmia by early afterdepolarization-induced triggered activity. Background. Early afterdepolarization-induced triggered activity has been suggested as an electrophysiologic mechanism for torsade de pointes. Consequently, the initiation of torsade de pointes should involve time- and rate-dependent alterations of ventricular repolarization similar to those known to modulate the development of early afterdepolarizations. Methods. RR and QT intervals were measured in digitized 24-h ambulatory electrocardiographic recordings obtained from seven patients with acquired prolongation of ventricular repolarization. Each patient had one or more episodes of torsade de pointes. The relation between RR and QT intervals was determined before, during and after multiple episodes of torsade de pointes. Results. In patients with multiple episodes of ventricular arrhythmias, the onset of the arrhythmias was associated with a critical prolongation of the QT interval. In some episodes, prolongation of the QT interval was associated with sudden prolongation of the sinus cycle length, whereas in other episodes, the QT interval prolonged progressively at a constant cycle length. Conclusions. The association between a critically prolonged QT interval and the onset of ventricular arrhythmias suggests that the initial complex of torsade de pointes is an early afterdepolarization-induced triggered response. However, prolongation of the QT interval itself was not sufficient to account for the initiation of torsade de pointes, suggesting that other, as yet unidentified factors are required. (J Am Coll Cardiol 1997;30:209–17

Comparison of automated interval measurements by widely used algorithms in digital electrocardiographs

Background: Automated measurements of electrocardiographic (ECG) intervals by current-generation digital electrocardiographs are critical to computer-based ECG diagnostic statements, to serial comparison of ECGs, and to epidemiological studies of ECG findings in populations. A previous study demonstrated generally small but often significant systematic differences among 4 algorithms widely used for automated ECG in the United States and that measurement differences could be related to the degree of abnormality of the underlying tracing. Since that publication, some algorithms have been adjusted, whereas other large manufacturers of automated ECGs have asked to participate in an extension of this comparison. Methods: Seven widely used automated algorithms for computer-based interpretation participated in this blinded study of 800 digitized ECGs provided by the Cardiac Safety Research Consortium. All tracings were different from the study of 4 algorithms reported in 2014, and the selected population was heavily weighted toward groups with known effects on the QT interval: included were 200 normal subjects, 200 normal subjects receiving moxifloxacin as part of an active control arm of thorough QT studies, 200 subjects with genetically proved long QT syndrome type 1 (LQT1), and 200 subjects with genetically proved long QT syndrome Type 2 (LQT2). Results: For the entire population of 800 subjects, pairwise differences between algorithms for each mean interval value were clinically small, even where statistically significant, ranging from 0.2 to 3.6 milliseconds for the PR interval, 0.1 to 8.1 milliseconds for QRS duration, and 0.1 to 9.3 milliseconds for QT interval. The mean value of all paired differences among algorithms was higher in the long QT groups than in normals for both QRS duration and QT intervals. Differences in mean QRS duration ranged from 0.2 to 13.3 milliseconds in the LQT1 subjects and from 0.2 to 11.0 milliseconds in the LQT2 subjects. Differences in measured QT duration (not corrected for heart rate) ranged from 0.2 to 10.5 milliseconds in the LQT1 subjects and from 0.9 to 12.8 milliseconds in the LQT2 subjects. Conclusions: Among current-generation computer-based electrocardiographs, clinically small but statistically significant differences exist between ECG interval measurements by individual algorithms. Measurement differences between algorithms for QRS duration and for QT interval are larger in long QT interval subjects than in normal subjects. Comparisons of population study norms should be aware of small systematic differences in interval measurements due to different algorithm methodologies, within-individual interval measurement comparisons should use comparable methods, and further attempts to harmonize interval measurement methodologies are warranted

QT interval and arrhythmic risk assessment after myocardial infarction

International audienceTo assess ventricular repolarization features as predictors of ventricular tachyarrhythmias (VT) in patients with previous myocardial infarction, we performed a dynamic study of QT interval from 24-hour electrocardiographic data. QT rate dependence was enhanced in patients with VT when compared with patients without VT

Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro-arrhythmia Assay initiative studies

Background and purpose: We evaluated the concordance of results from two sets of nonclinical cardiovascular safety studies on pitolisant. Experimental approach: Nonclinical studies envisaged both in the ICH S7B guideline and Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative were undertaken. CiPA-initiative studies included in vitro ion channels and stem cell-derived human ventricular myocyte studies as well as in silico modelling of results to simulate human ventricular electrophysiology. ICH S7B-recommended studies included in vitro hERG studies, in vivo dog study with follow-up investigations in rabbit Purkinje fibres and in vivo studies in the Carlsson rabbit proarrhythmia model. Key results: Both sets of nonclinical studies consistently excluded pitolisant from having clinically relevant QT-liability or proarrhythmic potential. CiPA studies revealed pitolisant to have modest calcium channel blocking and late I Na reducing activities at high concentrations, which resulted in reduction of dofetilide-induced early after-depolarisations (EADs) by pitolisantin ICH S7B studies. Studies in stem cell-derived human cardiomyocytes with dofetilide or E-4031 given alone and in combination with pitolisant confirmed these properties. In silico modelling confirmed that the measured ion channel effects are consistent with results from both the stem cell-derived cardiomyocyte and rabbit Purkinje fibre studies and categorised pitolisant as a drug with low torsadogenic potential. The results from the two sets of nonclinical studies correlated well with two clinical QT studies. Conclusions and implications: Our experience supports the CiPA initiative but suggests that sponsors should consider investigating drug effects on EADs and the use of proarrhythmia models when the results from CiPA studies are ambiguous

Management and monitoring recommendations for the use of eliglustat in adults with type 1 Gaucher disease in Europe

Purpose: In Gaucher disease, diminished activity of the lysosomal enzyme, acid β-glucosidase, leads to accumulation of glucosylceramides and related substrates, primarily in the spleen, liver, and bone marrow. Eliglustat is an oral substrate reduction therapy approved in the European Union and the United States as a first-line treatment for adults with type 1 Gaucher disease who have compatible CYP2D6 metabolism phenotypes. A European Advisory Council of experts in Gaucher disease describes the characteristics of eliglustat that are distinct from enzyme augmentation therapy (the standard of care) and miglustat (the other approved substrate reduction therapy) and recommends investigations and monitoring for patients on eliglustat therapy within the context of current recommendations for Gaucher disease management. Results: Eliglustat is a selective, potent inhibitor of glucosylceramide synthase, the enzyme responsible for biosynthesis of glucosylceramides which accumulate in Gaucher disease. Extensive metabolism of eliglustat by CYP2D6, and, to a lesser extent, CYP3A of the cytochrome P450 pathway, necessitates careful consideration of the patient's CYP2D6 metaboliser status and use of concomitant medications which share metabolism by these pathways. Guidance on specific assessments and monitoring required for eliglustat therapy, including an algorithm to determine eligibility for eliglustat, are provided. Conclusions: As a first-line therapy for type 1 Gaucher disease, eliglustat offers eligible patients a daily oral therapy alternative to biweekly infusions of enzyme therapy. Physicians will need to carefully assess individual Gaucher patients to determine their appropriateness for eliglustat therapy. The therapeutic response to eliglustat and use of concomitant medications will require long-term monitoring

Conditional Mineralocorticoid Receptor Expression in the Heart Leads to Life-Threatening Arrhythmias

International audienceBackground— Life-threatening cardiac arrhythmia is a major source of mortality worldwide. Besides rare inherited monogenic diseases such as long-QT or Brugada syndromes, which reflect abnormalities in ion fluxes across cardiac ion channels as a final common pathway, arrhythmias are most frequently acquired and associated with heart disease. The mineralocorticoid hormone aldosterone is an important contributor to morbidity and mortality in heart failure, but its mechanisms of action are incompletely understood. Methods and Results— To specifically assess the role of the mineralocorticoid receptor (MR) in the heart, in the absence of changes in aldosteronemia, we generated a transgenic mouse model with conditional cardiac-specific overexpression of the human MR. Mice exhibit a high rate of death prevented by spironolactone, an MR antagonist used in human therapy. Cardiac MR overexpression led to ion channel remodeling, resulting in prolonged ventricular repolarization at both the cellular and integrated levels and in severe ventricular arrhythmias. Conclusions— Our results indicate that cardiac MR triggers cardiac arrhythmias, suggesting novel opportunities for prevention of arrhythmia-related sudden death

An open-label study to investigate the cardiac safety profile of cabazitaxel in patients with advanced solid tumors

PURPOSE: This study assessed the cardiovascular safety of cabazitaxel, based on thorough evaluation of QT and non-QT variables, and the relationship between pharmacokinetic and pharmacodynamic electrocardiographic (ECG) profiles and the occurrence of Grade ≥3 cardiovascular adverse events. METHODS: Patients with advanced solid tumors were treated with cabazitaxel 25 mg/m(2) every 3 weeks. Digital ECG recordings were obtained during Cycle 1 over 24 h after dosing. The primary end point was effect of cabazitaxel on QT interval corrected by the Fridericia formula (QTcF). Secondary end points were additional ECG parameters (QT, PR and QRS intervals, and heart rate), plasma pharmacokinetics of cabazitaxel and overall clinical safety. RESULTS: The pharmacodynamic (ECG) population included 94 patients. In 63 patients with a full 24-h ECG evaluation, the maximum upper bound of 90 % confidence interval (CI) for mean QTcF change from baseline was 7.46 ms (mean 4.8 ms), occurring at 1 h 30 min post-infusion. The slope of QTcF change from baseline versus cabazitaxel concentration was slightly negative (-0.012 [95 % CI -0.017; -0.008], equivalent to a 1.2 ms decrease per 100 ng/mL increase in cabazitaxel concentration). For non-QT variables, no effect was noted. No Grade ≥3 cardiac adverse events were observed; Grade ≥3 hypotension and lymphocele occurred in two patients and one patient, respectively. CONCLUSION: These results suggest that cabazitaxel has no clinically significant cardiovascular adverse effects in patients with advanced solid tumors