An evaluation of a supratherapeutic dose of inclisiran on cardiac repolarization in healthy volunteers: A phase I, randomized study.

Inclisiran is a small interfering RNA molecule that has been shown to provide an effective and sustained reduction in low-density lipoprotein cholesterol levels. This study aimed to determine whether a supratherapeutic dose of inclisiran affects cardiac repolarization and conduction in healthy volunteers. A phase I, randomized, double-blind, double-dummy, placebo- and positive-controlled, three-way crossover study was performed in 48 healthy volunteers. Volunteers were assigned to three treatments in a randomized sequence: a supratherapeutic dose of inclisiran sodium (900 mg), placebo, or moxifloxacin 400 mg as a positive control, with a minimum 7-day washout period between treatments. Continuous electrocardiogram monitoring was performed from >60 min before dosing until 48 h after dosing. Pharmacokinetics, pharmacodynamics, and safety were also assessed. Inclisiran, at a supratherapeutic dose, did not show a clinically significant effect on the QT interval (Fridericia correction formula [QTcF]; maximal placebo- and baseline-corrected change: 2.5 ms [90% confidence interval: 0.6, 4.5]) near the maximal plasma concentrations at 4 h. In addition, inclisiran did not show any effects on other electrocardiogram intervals or ST- and T-wave morphology. The positive control, moxifloxacin, demonstrated the expected changes in QTcF interval, validating the adequate sensitivity of the study. A supratherapeutic dose of inclisiran sodium (900 mg) had no effect on the QTcF interval or other electrocardiogram parameters, providing additional insight and reassurance regarding the safety profile of inclisiran.

Amplifying Expertise in Rural West Virginia through Project ECHO: Impactful Partnerships and Community-Engagement.

BACKGROUND: Limited specialty care access is a major contributor to rural health disparities. Extensions for Community Healthcare Outcomes (ECHO) is an innovative training and education strategy to address the need for trained specialty care in rural areas, such as West Virginia (WV). This article describes the successful implementation of ECHO projects in diverse subject areas facilitated by unique partnerships between the WV Clinical and Translational Science Institute (WVCTSI) and its practice partners. WV Project ECHO aims to provide education and training in specialty areas through the use of technology and partnerships. METHODS: A case-based session coupled with a brief relevant didactic presentation is used to amplify rural provider specialty expertise through education of primary care physicians (PCPs) in specific clinical areas. Foundational partnerships and impact are described. CONCLUSIONS: Key lessons learned include leveraging existing partnerships and implementing projects based on provider needs. A unique result of WV Project ECHO is WV Medicaid's decision to accept case presentations made during the Hepatitis C ECHO session as the specialty consultation requirement (e.g., hepatologist or infectious diseases) for Medicaid coverage of hepatitis C drugs, thus increasing the number of patients receiving Hepatitis C treatment. A multi-partnered community approach facilitated by the widespread use of a technology-based provider education platform has facilitated the availability of curative therapy for a potentially fatal disease.

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.

West Virginia's model of buprenorphine expansion: Preliminary results.

West Virginia (WV) is situated at the epicenter of the opioid epidemic with the highest rates of overdose deaths and some of the lowest rates of access to life saving evidence-based medication assisted treatment (MAT) for patients with opioid use disorder (OUD). WV used a modified hub-and-spoke model to build organizational capacity for facilities to use buprenorphine to treat patients with OUD and to provide ongoing case consultation. The purpose of this study is to 1) describe the group-base model of buprenorphine treatment and the model used to build organizational capacity, 2) to describe the preliminary results of buprenorphine expansion in WV and 3) to report preliminary data describing and comparing the characteristics of the patients served across five hubs. A single Coordinating Center uses video conferencing to train hubs and provide ongoing case consultation, as well as clinical support. Hubs were trained to deliver a buprenorphine treatment model that is multi-disciplinary and includes group-based medication management and psychosocial therapy. Five regional hubs independently treat patients and are leading MAT expansion in their local areas by training and mentoring spokes (n = 13). As a result of the WV STR funding, 14 health care facilities have started to use buprenorphine, 56 health professionals were trained and 196 patients with OUD have been treated. There were few sociodemographic characteristic differences across patients treated at the five hubs, while there were differences in self-reported alcohol and drug use in the 30 days prior to intake. Additional research is needed to determine whether the WV modified hub-and-spoke model resulted in statistically significant improvements in buprenorphine treatment capacity; there is a need to address MAT stigma and regulatory barriers in order to ensure the long-term sustainability of the buprenorphine expansion.

Feasibility of a mHealth Approach to Nutrition Counseling in an Appalachian State.

West Virginia is a rural state with an aging population that may experience barriers to accessing nutritional and lifestyle counseling. This study examined feasibility of an online personalized nutrition tracking application, Good Measures (GM), with patients at seven health care clinics throughout the state. Fourteen healthcare providers and 64 patients 18 years or older with a Body Mass Index (BMI) greater than or equal to 30 and access to the Internet were recruited for this 12-week feasibility study. Patient participants logged meals and exercise into the GM application via smart phone, tablet, or computer and virtually engaged with a Registered Dietitian Nutritionist (RDN) in one-on-one sessions. The primary endpoint was to examine feasibility of the program by usage of the application and feedback questions regarding the benefits and challenges of the application. Participants were predominately white (92%) and female (76%). Minimal improvements in weight and systolic blood pressure were found. Participant attitude survey data declined from 4-weeks to 12-weeks of the intervention. Interestingly though, patients in a rural clinic had lesser declines in attitudes than peri-urban participants. Qualitative feedback data identified participants predominately had a positive overall feeling toward the approach. Participants expressed favorability of RDN access, the variety of foods, but did give suggestions for in-person meetings and more updating of the application. Implementing a technology approach to nutrition in rural areas of West Virginia using a mobile application with RDN access may be one strategy to address public health issues such as obesity.

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.

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.

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.

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.].

Mechanistic Model-Informed Proarrhythmic Risk Assessment of Drugs: Review of the "CiPA" Initiative and Design of a Prospective Clinical Validation Study.

The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a mechanistic-based assessment of the proarrhythmic risk of drugs. CiPA proposes to assess a drug's effect on multiple ion channels and integrate the effects in a computer model of the human cardiomyocyte to predict proarrhythmic risk. Unanticipated or missed effects will be assessed with human stem cell-derived cardiomyocytes and electrocardiogram (ECG) analysis in early phase I clinical trials. This article provides an overview of CiPA and the rationale and design of the CiPA phase I ECG validation clinical trial, which involves assessing an additional ECG biomarker (J-Tpeak) for QT prolonging drugs. If successful, CiPA will 1) create a pathway for drugs with hERG block / QT prolongation to advance without intensive ECG monitoring in phase III trials if they have low proarrhythmic risk; and 2) enable updating drug labels to be more informative about proarrhythmic risk, not just QT prolongation.

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.