Jose Vicente

Comprehensive T wave Morphology Assessment in a Randomized Clinical Study of Dofetilide, Quinidine, Ranolazine, and Verapamil

Background Congenital long QT syndrome type 2 (abnormal hERG potassium channel) patients can develop flat, asymmetric, and notched T waves. Similar observations have been made with a limited number of hERG‐blocking drugs. However, it is not known how additional calcium or late sodium block, that can decrease torsade risk, affects T wave morphology. Methods and Results Twenty‐two healthy subjects received a single dose of a pure hERG blocker (dofetilide) and 3 drugs that also block calcium or sodium (quinidine, ranolazine, and verapamil) as part of a 5‐period, placebo‐controlled cross‐over trial. At pre‐dose and 15 time‐points post‐dose, ECGs and plasma drug concentration were assessed. Patch clamp experiments were performed to assess block of hERG, calcium (L‐type) and late sodium currents for each drug. Pure hERG block (dofetilide) and strong hERG block with lesser calcium and late sodium block (quinidine) caused substantial T wave morphology changes (P<0.001). Strong late sodium current and hERG block (ranolazine) still caused T wave morphology changes (P<0.01). Strong calcium and hERG block (verapamil) did not cause T wave morphology changes. At equivalent QTc prolongation, multichannel blockers (quinidine and ranolazine) caused equal or greater T wave morphology changes compared with pure hERG block (dofetilide). Conclusions T wave morphology changes are directly related to amount of hERG block; however, with quinidine and ranolazine, multichannel block did not prevent T wave morphology changes. A combined approach of assessing multiple ion channels, along with ECG intervals and T wave morphology may provide the greatest insight into drug‐ion channel interactions and torsade de pointes risk. Clinical Trial Registration URL: http://clinicaltrials.gov/ Unique identifier: NCT01873950.

Assessing ECG signal quality indices to discriminate ECGs with artefacts from pathologically different arrhythmic ECGs.

False and non-actionable alarms in critical care can be reduced by developing algorithms which assess the trueness of an arrhythmia alarm from a bedside monitor. Computational approaches that automatically identify artefacts in ECG signals are an important branch of physiological signal processing which tries to address this issue. Signal quality indices (SQIs) derived considering differences between artefacts which occur in ECG signals and normal QRS morphology have the potential to discriminate pathologically different arrhythmic ECG segments as artefacts. Using ECG signals from the PhysioNet/Computing in Cardiology Challenge 2015 training set, we studied previously reported ECG SQIs in the scientific literature to differentiate ECG segments with artefacts from arrhythmic ECG segments. We found that the ability of SQIs to discriminate between ECG artefacts and arrhythmic ECG varies based on arrhythmia type since the pathology of each arrhythmic ECG waveform is different. Therefore, to reduce the risk of SQIs classifying arrhythmic events as noise it is important to validate and test SQIs with databases that include arrhythmias. Arrhythmia specific SQIs may also minimize the risk of misclassifying arrhythmic events as noise.

Investigation of potential mechanisms of sex differences in quinidine-induced torsade de pointes risk ☆

INTRODUCTION The electrocardiographic index Tpeak-Tend has been proposed as a marker of dispersion of repolarization and may be a stronger predictor of torsade de pointes risk than QTc prolongation. METHODS AND RESULTS We assessed whether quinidine-induced Tpeak-Tend prolongation is greater in women than men. The relationship between QTc prolongation and quinidine concentration was greater in women than men (38 ± 10 vs. 28 ± 9 ms/μg/ml, p=0.02), but there was no difference for Tpeak-Tend prolongation (39 ± 13 vs. 32 ± 13 ms/μg/ml, p=0.21). There was a delay (hysteresis) between peak concentration and both maximum QTc and Tpeak-Tend prolongation and a trend toward higher serum quinidine concentration in men than women. Analysis controlling for hysteresis showed no sex difference for QTc (55 ± 18 vs. 43 ± 19 ms/μg/ml, p=0.14), without changing the lack of sex difference with Tpeak-Tend (61 ± 22 vs. 55 ± 21 ms/μg/ml, p=0.49). CONCLUSIONS Women do not have a greater quinidine-induced Tpeak-Tend prolongation than men. Sex differences in hysteresis and serum quinidine concentration in this study may have contributed to sex differences in quinidine-induced QTc prolongation.

Sex differences in drug-induced changes in ventricular repolarization ☆

INTRODUCTION Heart rate corrected QT (QTc) interval prolongation is a predictor of drug-induced torsade de pointes, a potentially fatal ventricular arrhythmia that disproportionately affects women. This study assesses whether there are sex differences in the ECG changes induced by four different hERG potassium channel blocking drugs. METHODS AND RESULTS Twenty-two healthy subjects (11 women) received a single oral dose of dofetilide, quinidine, ranolazine, verapamil and placebo in a double-blind 5-period crossover study. ECGs and plasma drug concentrations were obtained at pre-dose and at 15 time-points post-dose. Dofetilide, quinidine and ranolazine prolonged QTc. There were no sex differences in QTc prolongation for any drug, after accounting for differences in exposure. Sex differences in any ECG biomarker were observed only with dofetilide, which caused greater J-Tpeakc prolongation (p=0.045) but lesser Tpeak-Tend prolongation (p=0.006) and lesser decrease of T wave amplitude (p=0.003) in women compared to men. CONCLUSIONS There were no sex differences in QTc prolongation for any of the studied drugs. Moreover, no systematic sex differences in other drug-induced ECG biomarker changes were observed in this study. This study suggests that the higher torsade risk in women compared to men is not due to a larger concentration-dependent QTc prolongation.

Comprehensive In Vitro Proarrhythmia Assay (CiPA) Update from a Cardiac Safety Research Consortium / Health and Environmental Sciences Institute / FDA Meeting

A Cardiac Safety Research Consortium / Health and Environmental Sciences Institute / FDA-sponsored Think Tank Meeting was convened in Washington, DC, on May 21, 2018, to bring together scientists, clinicians, and regulators from multiple geographic regions to evaluate progress to date in the Comprehensive In Vitro Proarrhythmia Assay (CiPA) Initiative, a new paradigm to evaluate proarrhythmic risk. Study reports from the 4 different components of the CiPA paradigm (ionic current studies, in silico modeling to generate a Torsade Metric Score, human induced pluripotent stem cell–derived ventricular cardiomyocytes, and clinical ECG assessments including J-Tpeakc) were presented and discussed. This paper provides a high-level summary of the CiPA data presented at the meeting.

A novel ECG detector performance metric and its relationship with missing and false heart rate limit alarms

PURPOSE Performance of ECG beat detectors is traditionally assessed on long intervals (e.g.: 30min), but only incorrect detections within a short interval (e.g.: 10s) may cause incorrect (i.e., missed+false) heart rate limit alarms (tachycardia and bradycardia). We propose a novel performance metric based on distribution of incorrect beat detection over a short interval and assess its relationship with incorrect heart rate limit alarm rates. BASIC PROCEDURES Six ECG beat detectors were assessed using performance metrics over long interval (sensitivity and positive predictive value over 30min) and short interval (Area Under empirical cumulative distribution function (AUecdf) for short interval (i.e., 10s) sensitivity and positive predictive value) on two ECG databases. False heart rate limit and asystole alarm rates calculated using a third ECG database were then correlated (Spearmans rank correlation) with each calculated performance metric. MAIN FINDINGS False alarm rates correlated with sensitivity calculated on long interval (i.e., 30min) (ρ=-0.8 and p<0.05) and AUecdf for sensitivity (ρ=0.9 and p<0.05) in all assessed ECG databases. Sensitivity over 30min grouped the two detectors with lowest false alarm rates while AUecdf for sensitivity provided further information to identify the two beat detectors with highest false alarm rates as well, which was inseparable with sensitivity over 30min. PRINCIPAL CONCLUSIONS Short interval performance metrics can provide insights on the potential of a beat detector to generate incorrect heart rate limit alarms.