Surface Electrocardiographic Parameters of Children and Adolescents Diagnosed with Attention-Deficit/Hyperactivity Disorder in an Ambulatory Community Pediatric Center: A Focus on Cardiac Repolarization Electrocardiogram Intervals.

Objectives: Our research aims were to determine if repolarization measures (QTcF, QTcB, JTcF, and JTcB) in attention-deficit/hyperactivity disorder (ADHD) children and adolescents differ from normal subjects and determine if the JTc interval duration, as a purer repolarization measure than QTc, strengthens the differentiation between ADHD and normal children and adolescents. Methods: This study included 418 subjects aged 5-18 years who were diagnosed with ADHD, and 1948 subjects in a historical normal control group. One-way analysis of variance (ANOVA) was performed to compare the independent groups on normal continuous outcomes. Means and standard deviations (SDs) were reported and interpreted for the ANOVA. Logistic regression analysis was performed to test the ability of four variables (QTcB, QTcF, JTcB, and JTcF) to predict an ADHD diagnosis, with age and gender as independent covariates. The log odds with standard errors for each variable were reported and interpreted for the logistic models. Results: In the nominal logistic regressions with JTcF ≥322 or JTcB ≥335 (values 1 SD above the mean of the control group), age and sex were significant contributors to the models that showed that subjects with a JTcF ≥322 ms had a statistically and significantly higher probability to be diagnosed with ADHD in comparison with normal control subjects (odds ratio [OR]: 2.6, 95% confidence interval [95% CI] 2.02-3.33, p < 0.0001). Similarly, those subjects with a JTcB ≥335 ms were 2.7 times more likely to be diagnosed with ADHD than normal control subjects (OR: 2.7, 95% CI 2.1-3.45, p < 0.0001). Conclusions: JTc provided a clearer separation of the groups than QTc. JTcB and JTcF 1 SD above the control group means are strong predictors of ADHD diagnosis and remain so even when strong demographic predictors of longer QTc (age and sex) are included in the regression models. Consideration should be given to recording a pretreatment electrocardiogram in all children and adolescents with ADHD, and to measuring and monitoring JTc in patients with ADHD, especially when considering the addition of QT prolonging drugs.

Immunoglobulin free light chains as an inflammatory biomarker of heart failure with myocarditis.

BACKGROUND: In this study, we measured immunoglobulin free light chains (FLC), a biomarker of inflammation in the sera of patients with heart failure due to myocarditis. METHODS: FLC kappa and FLC lambda were assayed in stored serum samples from patients with heart failure with myocarditis from the US myocarditis treatment trial by a competitive-inhibition multiplex Luminex® assay. RESULTS: The median concentration of circulating FLC kappa/lambda ratio was significantly lower in the sera from patients with heart failure with myocarditis than in healthy controls, and FLC kappa/lambda ratio had good diagnostic ability for identification of heart failure with myocarditis. Further, FLC kappa/lambda ratio was an independent prognostic factor for overall survival, and allowed creation of three prognostic groups by combining with N-terminal pro-B-type natriuretic peptide. CONCLUSIONS: This study suggests that FLC kappa/lambda ratio is a promising biomarker of heart failure with myocarditis.

Effect of Cefiderocol, a Siderophore Cephalosporin, on QT/QTc Interval in Healthy Adult Subjects.

PURPOSE: Cefiderocol is a novel siderophore cephalosporin with potent activity against gram-negative bacteria, including multidrug-resistant strains. This Phase I study was conducted to assess the tolerability of single-ascending doses of cefiderocol (part 1) and the effect of cefiderocol on cardiac repolarization, assessed using the electrocardiographic corrected QT interval (QTcF) and other ECG parameters (part 2), in healthy adult subjects. METHODS: Part 1 was a randomized, double-blind, placebo-controlled, single-ascending dose study in healthy adult male and female subjects. Part 2 was a 4-period crossover study in which subjects received a single 2-g dose of cefiderocol (therapeutic dose), a single 4-g dose of cefiderocol (supratherapeutic dose), or saline (placebo), each infused over 3 hours, and a single oral 400-mg dose of moxifloxacin. In each treatment period, continuous cardiac monitoring was used to assess the effects of cefiderocol on ECG parameters. The QT interval corrected using the Fridericia formula (QTcF) was the primary ECG parameter; the time-matched placebo- and baseline-adjusted (dd)-QTcF interval was the primary end point. The plasma pharmacokinetic properties of cefiderocol were calculated on the basis of concentration-time profiles in all evaluable subjects. FINDINGS: All point estimates for the ddQTcF interval were <5 ms and the upper bound of the 90% CIs were <10 ms at each timepoint after the initiation of the cefiderocol 3-hour infusion. Concentration-effect modeling showed a slightly negative slope and predicted modestly negative values of the ddQTcF interval at the Cmax of cefiderocol. Both doses of cefiderocol were well tolerated. All adverse events were mild in severity, with no deaths or serious adverse events reported. IMPLICATIONS: Overall, therapeutic and supratherapeutic doses of cefiderocol had no apparent clinically significant effect on the QTcF.

Correction of the QRS duration for heart rate.

OBJECTIVE: To determine the clinical value of correcting the QRS duration for heart rate. BACKGROUND: We recently observed [1] that the QRS duration shortens during spontaneous increases in heart rate. In the current study, we analyzed ECG and pharmacokinetic data of 21 subjects who received quinidine in a recent study [2]. They experienced the expected post-quinidine increase in heart rate, allowing us to determine if quinidine's well-known QRS prolongation might be attenuated due to the concomitant rate increase. METHODS: In a crossover-designed study, after baseline ECG recording, the subjects received quinidine 400 mg orally or placebo, and ECGs and quinidine plasma concentrations were then obtained at 15 prespecified timepoints over 24 h. The previously determined QRS-RR regression slope (0.0125) [1] was used to rate-correct QRS. Change in QRS from baseline (dQRS) and rate-corrected change in QRS from baseline (dQRSc) over time were plotted with the mean quinidine concentration and the correlation of plasma concentration with dQRS and dQRSc was assessed by pairwise correlation and linear regression. RESULTS: There was a statistically significantly greater increase in heart rate at all timepoints combined in the quinidine arm compared with the placebo arm (9.9 ±â€¯6.80 vs. 5.2 ±â€¯7.42, respectively, p < 0.0001). dQRSc was significantly greater at all timepoints combined compared with dQRS (1.99 ±â€¯4.824 vs -0.68 ±â€¯4.640 msec, respectively, p < 0.0001). dQRS correlated poorly with quinidine plasma concentration (p = 0.127), with no clear change in QRS observed. On the other hand, dQRSc correlated well with quinidine concentration (p = 0.010), with a clear rise and fall in dQRSc that mirrored the rise and fall of quinidine concentration. CONCLUSION: Rate correction of the QRS duration improves detection of QRS prolongation in the presence of heart rate change. CONDENSED ABSTRACT: Using the mean QRS - RR slope determined previously in normal volunteers [1], we corrected the QRS duration for its known dependency on heart rate in 21 subjects who received quinidine and experienced the expected post-quinidine increase in heart rate in a recent clinical trial [2]. We found that uncorrected QRS did not correlate with quinidine concentration (p = 0.127), while rate-corrected QRS correlated well (p = 0.010) and mirrored the rise and fall of quinidine concentration. Rate correction of the QRS duration improves detection of QRS prolongation in the presence of heart rate change.

Salutary Effects of the PULVAD, a Novel Implantable Counterpulsation Assist Device, on Cardiac Mechanoenergetics.

The Pressure Unloading Left Ventricular Assist Vevice (PULVAD) is a novel implantable counterpulsation LVAD, designed to provide ventricular unloading with augmentation of LV performance and retention of pulsatility. We assessed the effects of the PULVAD on hemodynamics and LV mechanoenergetics in seven farm pigs with acute ischemic heart failure. The PULVAD was implanted in the thorax and was connected to the ascending aorta. The PULVAD was pneumatically driven by a standard intra-aortic balloon pump console and was electrocardiogram-synchronized to provide LV pressure unloading along with diastolic aortic pressure augmentation. Hemodynamics, indices of LV mechanoenergetics, and coronary blood flow were measured without and after brief PULVAD support. PULVAD support decreased LV afterload and improved LV mechanical performance (increased ejection fraction, stroke volume, cardiac output and maximum elastance). The PULVAD concurrently reduced LV energy consumption (decreased stroke work and pressure-volume area) and optimized LV energetic performance (improved the ratio of stroke work to pressure-volume area). PULVAD support increased mean coronary blood flow, through dramatic augmentation of diastolic blood flow. In conclusion, the PULVAD unloads the failing LV, optimizes LV mechanoenergetics, and augments coronary blood flow. These salutary effects of short-term PULVAD support provide the foundation for long-term testing.

Comparison of Electrocardiographic Biomarkers for Differentiating Drug-Induced Single vs. Multiple Cardiac Ion Channel Block.

Since introduction of the International Conference on Harmonization proarrhythmia guidelines in 2005, no new marketed drugs have been associated with unacceptable risk of Torsade de Pointes. Although cardiac safety improved, these guidelines had the unintended consequence of eliminating potentially beneficial drugs from pipelines early in development. More recently, it has been shown that a corrected QT (QTc) prolonging drug may be safe if it impacts multiple ion channels vs. only human ether-a-go-go related gene (hERG) and that this effect can be discriminated using QT subintervals. We compared the predictive power of four electrocardiogram (ECG) repolarization metrics to discriminate single vs. multichannel block: (i) traditional 10-second signal averaged triplicates, and (ii) three metrics that used increasing density of automatically measured beat-to-beat (btb) intervals. Predictive power was evaluated using logistic regression and quantified with receiver operating characteristic (ROC) area under the curve (AUC). Compared with the traditional 10-second signal averaged triplicates, the reduction in classification error ranged from 2-6 with increasing density of btb measurements.

Assessment of Multi-Ion Channel Block in a Phase I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study.

Balanced multi-ion channel-blocking drugs have low torsade risk because they block inward currents. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative proposes to use an in silico cardiomyocyte model to determine the presence of balanced block, and absence of heart rate corrected J-Tpeak (J-Tpeak c) prolongation would be expected for balanced blockers. This study included three balanced blockers in a 10-subject-per-drug parallel design; lopinavir/ritonavir and verapamil met the primary end point of ΔΔJ-Tpeak c upper bound < 10 ms, whereas ranolazine did not (upper bounds of 8.8, 6.1, and 12.0 ms, respectively). Chloroquine, a predominant blocker of the potassium channel encoded by the ether-à-go-go related gene (hERG), prolonged ΔΔQTc and ΔΔJ-Tpeak c by ≥ 10 ms. In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide-induced ΔQTc prolongation, but shortened ΔJ-Tpeak c and prolonged ΔTpeak -Tend . Absence of J-Tpeak c prolongation seems consistent with balanced block; however, small sample size (10 subjects) may be insufficient to characterize concentration-response in some cases.

Electrocardiographic Effects of a Supratherapeutic Dose of WCK 2349, a Benzoquinolizine Fluoroquinolone.

The purpose of this study was to measure the electrocardiographic (ECG) effects of WCK 2349 (the L-alanine ester prodrug of levonadifloxacin) at a supratherapeutic oral dose of 2,600 mg. A total of 48 healthy volunteers were randomized to treatment with placebo, WCK 2349, or oral moxifloxacin, 400 mg, in a crossover-designed thorough QT study. A supratherapeutic mean maximum levonadifloxacin concentration (Cmax ) of 43.3 µg/mL was achieved at 3.1 hours. A therapeutic dose of 1,000 mg b.i.d. in a previous study in patients resulted in a Cmax of 17.8 µg/mL. WCK 2349 exerted no significant effect on baseline- and placebo-corrected QTcF (QT interval corrected for heart rate (HR) by the Fridericia formula), QRS, or PR interval. HR was transiently accelerated by a maximum of 14.4 (95% confidence interval, 11.80-16.92) beats per minute (bpm) at 3 hours. Concentration-effect modeling predicted a mean increase of 8.0 bpm at Cmax at the standard therapeutic dose. A therapeutic dose of 1,000 mg b.i.d. of WCK 2349 is not expected to cause clinically significant ECG effects, except for a possible transient increase in HR, which seems to be clinically insignificant.

Evaluation of the Cardiac Safety of Long-Acting Endectocide Moxidectin in a Randomized Concentration-QT Study.

Potential effects on cardiac repolarization of single doses of moxidectin, a potent long-acting macrocyclic lactone endectocide, were assessed in a concentration-QT (c-QT; exposure-response) study. This double-blind, placebo-controlled, parallel-group study in healthy male volunteers (n = 60) randomized subjects to a single oral dose of moxidectin (4 mg, 8 mg, 16 mg, 24 mg, or 36 mg) or matching placebo. Serial plasma samples for pharmacokinetic (PK) analysis and concurrent triplicate electrocardiogram measurements were taken at baseline and 14 prespecified time points over 72 hours, yielding 900 QT interval-plasma concentration time-matched pairs. Moxidectin had no statistically significant or clinically relevant impact on QT interval at any dose level. The primary mixed effects model analysis revealed no treatment-related impact on the Fridericia-corrected QT interval-plasma concentration gradient (-0.0077, 90% confidence interval (CI) -0.0255 to +0.0101).

Correction: Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block.

[This corrects the article DOI: 10.1371/journal.pone.0163619.].

Comparison of Two Highly Automated ECG Algorithms for Detection of Drug-Induced Cardiac Ion Channel Block.

US Food and Drug Administration (FDA) investigators recently demonstrated in a crossover study that early (J-Tpeak c) and late (Tpeak -Tend ) repolarization duration can differentiate selective potassium block with a high arrhythmia risk from multichannel block with lower risk in subjects receiving dofetilide, verapamil, quinidine, or ranolazine. The purpose of this study was to determine if the findings by the FDA using their published software algorithm could be corroborated using an alternative software algorithm for the same metrics and to determine if methodological differences resulted in clinically meaningful differences in interpretation. Exposure-response relationships computed with linear mixed effects models and mean maximal effects on ECG intervals measured by the two algorithms were similar, corroborating the FDA findings, but with some differences in the modeled slopes and magnitude of changes. The alternative software resulted in an average 25% reduction in the 95% confidence intervals of the mixed effects models with generally lower Akaike Information Criterion values.

Debatable issues in automated ECG reporting.

Although automated ECG analysis has been available for many years, there are some aspects which require to be re-assessed with respect to their value while newer techniques which are worthy of review are beginning to find their way into routine use. At the annual International Society of Computerized Electrocardiology conference held in April 2017, four areas in particular were debated. These were a) automated 12 lead resting ECG analysis; b) real time out of hospital ECG monitoring; c) ECG imaging; and d) single channel ECG rhythm interpretation. One speaker presented the positive aspects of each technique and another outlined the more negative aspects. Debate ensued. There were many positives set out for each technique but equally, more negative features were not in short supply, particularly for out of hospital ECG monitoring.

Cardiologist's point of view: Novel ECG biomarkers and in silico models for proarrhythmic risk prediction: Are we ready?

The CiPA initiative is well underway, but in its early stages. Are we ready for it? There are several issues that bear on the success of this multidisciplinary effort related to (1) the final testing paradigm that will result, (2) the way in which discrepancies in test methods will be handled, (3) commercialization of the testing methods, (4) quantitative understanding of arrhythmia risk of the 6 non-hERG channels being tested, (5) validity of the CiPA drug list, and (6) ultimate clinical validation.

Antimicrobials and QT prolongation.

Solithromycin, a ketolide/macrolide antibiotic, has recently been reported to be free of the expected QT-prolonging effect of macrolides. It appears that its keto substitution provides a structural basis for this observation, as the other two tested ketolides also have minimal QT effect.Among non-cardiovascular therapies, antimicrobials probably carry the greatest potential to cause cardiac arrhythmias. This is a result of their propensity to bind to the delayed rectifier potassium channel, IKr, inducing QT prolongation and risk of torsades de pointes ventricular tachycardia, their frequent interference with the metabolism of other QT prolongers and their susceptibility to metabolic inhibition by numerous commonly used drugs.Unfortunately, there is evidence that medical practitioners do not take account of the QT/arrhythmia risk of antimicrobials in their prescribing practices. Education on this topic is sorely needed. When a macrolide is indicated, a ketolide should be considered in patients with a QT risk.

Common Genetic Variant Risk Score Is Associated With Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study.

BACKGROUND: Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known. METHODS: We tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs. Genetic analysis of 22 subjects was performed in a secondary analysis of a randomized, double-blind, placebo-controlled, crossover trial of 3 QT-prolonging drugs with 15 time-matched QT and plasma drug concentration measurements. Subjects received single doses of dofetilide, quinidine, ranolazine, and placebo. The outcome was the correlation between a genetic QT score comprising 61 common genetic variants and the slope of an individual subject's drug-induced increase in heart rate-corrected QT (QTc) versus drug concentration. RESULTS: The genetic QT score was correlated with drug-induced QTc prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide (r=0.55; 95% confidence interval, 0.09-0.81; P=0.02), 23% in response to quinidine (r=0.48; 95% confidence interval, -0.03 to 0.79; P=0.06), and 27% in response to ranolazine (r=0.52; 95% confidence interval, 0.05-0.80; P=0.03). Furthermore, the genetic QT score was a significant predictor of drug-induced torsade de pointes in an independent sample of 216 cases compared with 771 controls (r2=12%, P=1×10-7). CONCLUSIONS: We demonstrate that a genetic QT score comprising 61 common genetic variants explains a significant proportion of the variability in drug-induced QT prolongation and is a significant predictor of drug-induced torsade de pointes. These findings highlight an opportunity for recent genetic discoveries to improve individualized risk-benefit assessment for pharmacological therapies. Replication of these findings in larger samples is needed to more precisely estimate variance explained and to establish the individual variants that drive these effects. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01873950.

Moxifloxacin Increases Heart Rate in Humans.

(1) Background: We assessed the effect of moxifloxacin on heart rate, and reviewed the heart rate effects of other antibiotics; (2) Methods: A total of 335 normal volunteers had 12-lead electrocardiograms recorded at multiple time points before and during treatment with moxifloxacin and with placebo in seven consecutive, thorough QT studies of crossover design; (3) Results: The average baseline heart rate across the seven studies was 61.5 bpm. The heart rate after moxifloxacin dosing was analyzed at five time points shared by all seven studies (hours 1, 2, 3, 12 and 24). The maximum mean heart rate (HR) increase for the seven studies combined was 2.4 bpm (95% CI 1.6, 3.3) at hour 2. The range of mean maximum increases among the seven studies was 2.1 to 4.3 bpm. For the seven studies combined, the increase was statistically significant at all but the 24 h time point. The maximum observed individual increase in HR was 36 bpm and the mean maximum increase was 30 ± 4.1 bpm by time point and 8 ± 6.9 bpm by subject. Many antibiotics increase HR, some several-fold more than moxifloxacin. However, clinicians and clinical investigators give little attention to this potential adverse effect in the medical literature; (4) Conclusions: The observed moxifloxacin-induced increase in HR is large enough to be clinically relevant, and it is a potentially important confounder in thorough QT studies using moxifloxacin as an active control. More attention to heart rate effects of antibiotics is warranted.

Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block.

BACKGROUND: Drugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Thus, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the "CiPA" initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans. METHODS AND RESULTS: In this study we assess the ability of eight ECG morphology biomarkers to detect late sodium current block in the presence of QTc prolongation by analyzing a clinical trial where a selective hERG potassium channel blocker (dofetilide) was administered alone and then in combination with two late sodium current blockers (lidocaine and mexiletine). We demonstrate that late sodium current block has the greatest effect on the heart-rate corrected J-Tpeak interval (J-Tpeakc), followed by QTc and then T-wave flatness. Furthermore, J-Tpeakc is the only biomarker that improves detection of the presence of late sodium current block compared to using QTc alone (AUC: 0.83 vs. 0.72 respectively, p<0.001). CONCLUSIONS: Analysis of the J-Tpeakc interval can differentiate drug-induced multichannel block involving the late sodium current from selective hERG potassium channel block. Future methodologies assessing drug effects on cardiac ion channel currents on the ECG should use J-Tpeakc to detect the presence of late sodium current block. TRIAL REGISTRATION: NCT02308748 and NCT01873950.

Electrocardiographic Effects of a Supratherapeutic Dose of Oritavancin.

The purpose of this study was to measure oritavancin's electrocardiographic effects at a supratherapeutic dose of 1600 mg given intravenously (IV) over 3 hours. A cohort of 150 healthy volunteers were randomized to receive placebo, oritavancin, or oral moxifloxacin 400 mg in a parallel designed thorough QT study. A supratherapeutic mean maximum oritavancin concentration (Cmax ) of 232 µg/mL was achieved. There was no significant effect on baseline and placebo corrected (dd) QTcF, QRS, or heart rate; ddPR was slightly increased at most time points, with a maximum mean change of 7.7 milliseconds 1 hour after infusion. Linear PK-PD modeling predicted a 3.2-millisecond change in the PR interval for the Cmax (138 µg/mL) observed in pivotal phase 3 studies after 1200 mg of oritavancin. Moxifloxacin produced the expected increase in ddQTcF, validating assay sensitivity. At plasma concentrations above the clinical exposures of oritavancin, no clinically or statistically significant effect on QTcF, QRS, or heart rate was observed. The increase in PR is considered clinically insignificant, given the rapid decline in initial plasma concentration of oritavancin after infusion and the expected lower Cmax in patients. A therapeutic 1200-mg single dose of oritavancin is not anticipated to cause any clinically significant effect on cardiac electrophysiology.

A fundamental relationship between intraventricular conduction and heart rate.

BACKGROUND: Existence of a relationship between the electrocardiographic QRS interval duration and the diurnally varying heart rate, of consistent sign and magnitude, is controversial and the relationship has not been fully characterized in normal populations. METHODS AND RESULTS: We analyzed the QRS-RR interval relationship in 884 Holter recordings in 410 normal subjects participating in 5 clinical trials. The slope of the linear regression of QRS on RR was positive in 93% of subjects with an average slope of 0.0125, which indicates an increase in QRS duration of 1.25msec for an increase in RR interval of 100msec. The increase was 15% larger in women than in men. Age had no significant effect on the slope. CONCLUSIONS: In two populations of normal subjects we observed a robust, direct relationship between the spontaneously changing RR interval and intraventricular conduction time represented by the duration of the QRS interval. As heart rate increases, QRS duration decreases. The change is larger in women. These observations have important physiological and clinical implications.