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Journal of Pharmacological and... 2024A recent paradigm shift in proarrhythmic risk assessment suggests that the integration of clinical, non-clinical, and computational evidence can be used to reach a...
BACKGROUND AND PURPOSE
A recent paradigm shift in proarrhythmic risk assessment suggests that the integration of clinical, non-clinical, and computational evidence can be used to reach a comprehensive understanding of the proarrhythmic potential of drug candidates. While current computational methodologies focus on predicting the incidence of proarrhythmic events after drug administration, the objective of this study is to predict concentration-response relationships of QTc as a clinical endpoint.
EXPERIMENTAL APPROACH
Full heart computational models reproducing human cardiac populations were created to predict the concentration-response relationship of changes in the QT interval as recommended for clinical trials. The concentration-response relationship of the QT-interval prolongation obtained from the computational cardiac population was compared against the relationship from clinical trial data for a set of well-characterized compounds: moxifloxacin, dofetilide, verapamil, and ondansetron.
KEY RESULTS
Computationally derived concentration-response relationships of QT interval changes for three of the four drugs had slopes within the confidence interval of clinical trials (dofetilide, moxifloxacin and verapamil) when compared to placebo-corrected concentration-ΔQT and concentration-ΔQT regressions. Moxifloxacin showed a higher intercept, outside the confidence interval of the clinical data, demonstrating that in this example, the standard linear regression does not appropriately capture the concentration-response results at very low concentrations. The concentrations corresponding to a mean QTc prolongation of 10 ms were consistently lower in the computational model than in clinical data. The critical concentration varied within an approximate ratio of 0.5 (moxifloxacin and ondansetron) and 1 times (dofetilide, verapamil) the critical concentration observed in human clinical trials. Notably, no other in silico methodology can approximate the human critical concentration values for a QT interval prolongation of 10 ms.
CONCLUSION AND IMPLICATIONS
Computational concentration-response modelling of a virtual population of high-resolution, 3-dimensional cardiac models can provide comparable information to clinical data and could be used to complement pre-clinical and clinical safety packages. It provides access to an unlimited exposure range to support trial design and can improve the understanding of pre-clinical-clinical translation.
Topics: Humans; Dose-Response Relationship, Drug; Electrocardiography; Fluoroquinolones; Heart Rate; Long QT Syndrome; Moxifloxacin; Ondansetron; Phenethylamines; Sulfonamides; Verapamil
PubMed: 38432528
DOI: 10.1016/j.vascn.2024.107498 -
Sensors (Basel, Switzerland) Feb 2024In the rapidly evolving landscape of continuous electrocardiogram (ECG) monitoring systems, there is a heightened demand for non-invasive sensors capable of measuring... (Review)
Review
In the rapidly evolving landscape of continuous electrocardiogram (ECG) monitoring systems, there is a heightened demand for non-invasive sensors capable of measuring ECGs and detecting heart rate variability (HRV) in diverse populations, ranging from cardiovascular patients to sports enthusiasts. Challenges like device accuracy, patient privacy, signal noise, and long-term safety impede the use of wearable devices in clinical practice. This scoping review aims to assess the performance and safety of novel multi-channel, sensor-based biopotential wearable devices in adults. A comprehensive search strategy was employed on four databases, resulting in 143 records and the inclusion of 12 relevant studies. Most studies focused on healthy adult subjects ( = 6), with some examining controlled groups with atrial fibrillation (AF) ( = 3), long QT syndrome ( = 1), and sleep apnea ( = 1). The investigated bio-sensor devices included chest-worn belts ( = 2), wrist bands ( = 2), adhesive chest strips ( = 2), and wearable textile smart clothes ( = 4). The primary objective of the included studies was to evaluate device performance in terms of accuracy, signal quality, comparability, and visual assessment of ECGs. Safety findings, reported in five articles, indicated no major side effects for long-term/continuous monitoring, with only minor instances of skin irritation. Looking forward, there are ample opportunities to enhance and test these technologies across various physical activity intensities and clinical conditions.
Topics: Adult; Humans; Wearable Electronic Devices; Electrocardiography; Heart Rate; Monitoring, Physiologic; Atrial Fibrillation
PubMed: 38400474
DOI: 10.3390/s24041318 -
Journal of Pharmacological Sciences Mar 2024An injectable anti-influenza drug peramivir has been reported to induce QT-interval prolongation in some phase III studies, although its thorough QT/QTc study was...
An injectable anti-influenza drug peramivir has been reported to induce QT-interval prolongation in some phase III studies, although its thorough QT/QTc study was negative. We investigated the discrepancy among those clinical studies using isoflurane-anesthetized beagle dogs (n = 4). Peramivir in doses of 1 mg/kg/10 min (sub-therapeutic dose) followed by 10 mg/kg/10 min (clinically-relevant dose) was intravenously administered. Peramivir prolonged QT interval/QTcV and T-T, and tended to delay ventricular repolarization in a reverse-frequency dependent manner, indicating I inhibition in vivo. Meanwhile, peramivir did not alter P-wave duration, PR interval or QRS width, indicating a lack of impact on cardiac conduction via Na or Ca channel inhibition in vivo. Peramivir prolonged T-T and tended to prolong terminal repolarization period, which would develop substrates for initiating and maintaining spiral reentry, respectively. Meanwhile, peramivir did not prolong J-Tc, which could not induce early afterdepolarization, a trigger inducing torsade de pointes. Thus, our results support that clinical dose exposure of peramivir can delay the ventricular repolarization in influenza patients. Peramivir has only a small potential to induce torsade de pointes in patients with the intact hearts, but caution should be paid on its use for patients formerly having the trigger for torsade de pointes.
Topics: Humans; Dogs; Animals; Torsades de Pointes; Isoflurane; Influenza, Human; Heart; Long QT Syndrome; Electrocardiography; Acids, Carbocyclic; Guanidines
PubMed: 38395523
DOI: 10.1016/j.jphs.2024.02.002 -
SAGE Open Medical Case Reports 2024Remdesivir is a nucleotide prodrug of an adenosine analog. It binds to the viral Ribonucleic Acid (RNA)-dependent RNA polymerase and inhibits viral replication by...
Remdesivir is a nucleotide prodrug of an adenosine analog. It binds to the viral Ribonucleic Acid (RNA)-dependent RNA polymerase and inhibits viral replication by terminating RNA transcription prematurely. Remdesivir has demonstrated in vitro and in vivo activity against Severe Acute Respiratory Syndrome Coronavirus 2; it also acts in vitro neutralization activity against the Omicron variant and its subvariants. We reported a 54-years-old woman admitted with Coronavirus disease 2019. Considering to require a high fraction of inspired oxygen therapy (⩾0.6) and based on lung high resolution computed tomography, Remdesivir therapy was ordered for 5 days. She experienced palpitations and dizziness 2 days after starting Remdesivir therapy. Her QTc interval was prolonged on the electrocardiogram without any significant electrolyte abnormalities or concomitant use of medications. Although the cardiac side effects of Remdesivir therapy have been well documented, in a few cases reported the association between Remdesivir therapy and QTc interval prolongation. Since, QTc interval prolongation has the potential risk of sudden cardiac death, the clinicians should be aware of mentioned association and check electrocardiogram daily, as well as other laboratory exams.
PubMed: 38384983
DOI: 10.1177/2050313X241233432 -
JACC. Case Reports Feb 2024We describe the case of an asymptomatic young pregnant woman with a diagnosis of congenital long QT syndrome type II in the context of in utero fetal 2:1 heart block and...
We describe the case of an asymptomatic young pregnant woman with a diagnosis of congenital long QT syndrome type II in the context of in utero fetal 2:1 heart block and ventricular tachycardia. The presentation, clinical considerations, and management of the mother and baby in the antepartum and postpartum periods are discussed.
PubMed: 38379654
DOI: 10.1016/j.jaccas.2023.102218 -
MedRxiv : the Preprint Server For... Jun 2024Long QT syndrome (LQTS) is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by . Variant...
BACKGROUND
Long QT syndrome (LQTS) is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by . Variant classification is difficult, often owing to lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance. Here, we sought to test whether variant-specific information, primarily from high-throughput functional assays, could improve both classification and cardiac event risk stratification in a large, harmonized cohort of missense variant heterozygotes.
METHODS
We quantified cell-surface trafficking of 18,796 variants in using a Multiplexed Assay of Variant Effect (MAVE). We recorded KCNH2 current density for 533 variants by automated patch clamping (APC). We calibrated the strength of evidence of MAVE data according to ClinGen guidelines. We deeply phenotyped 1,458 patients with missense variants, including QTc, cardiac event history, and mortality. We correlated variant functional data and Bayesian LQTS penetrance estimates with cohort phenotypes and assessed hazard ratios for cardiac events.
RESULTS
Variant MAVE trafficking scores and APC peak tail currents were highly correlated (Spearman Rank-order ρ = 0.69). The MAVE data were found to provide up to evidence for severe loss-of-function variants. In the cohort, both functional assays and Bayesian LQTS penetrance estimates were significantly predictive of cardiac events when independently modeled with patient sex and adjusted QT interval (QTc); however, MAVE data became non-significant when peak-tail current and penetrance estimates were also available. The area under the ROC for 20-year event outcomes based on patient-specific sex and QTc (AUC 0.80 [0.76-0.83]) was improved with prospectively available penetrance scores conditioned on MAVE (AUC 0.86 [0.83-0.89]) or attainable APC peak tail current data (AUC 0.84 [0.81-0.88]).
CONCLUSION
High throughput variant MAVE data meaningfully contribute to variant classification at scale while LQTS penetrance estimates and APC peak tail current measurements meaningfully contribute to risk stratification of cardiac events in patients with heterozygous missense variants.
CLINICAL PERSPECTIVE
A two-order of magnitude increase in the set of calibrated functional data for -LQTS is provided by two complementary assays Proactively available variant scores are presented for all possible missense variants by using a LQTS penetrance estimation framework conditioned on high-throughput MAVE dataVariant functional data, in addition to patient features of corrected QT interval and sex, significantly improve modeling of 20-year cardiac event outcomes Readily available MAVE scores for thousands of variants may facilitate classification of new variants discovered in individuals with suspected LQTS Scores and penetrance estimates are readily searchable at variantbrowser.org for community inquiry Both automated patch-clamp data and quantitative LQTS penetrance estimates, conditioned on MAVE data, improve prediction of 20-year cardiac event outcomes in a large cohort of heterozygotes.
PubMed: 38370760
DOI: 10.1101/2024.02.01.24301443 -
JACC. Case Reports Feb 2024A low baseline fetal heart rate at 20 weeks' gestation was detected in a fetus without cardiac structural anomalies. Fetal echocardiography and magnetocardiography were...
A low baseline fetal heart rate at 20 weeks' gestation was detected in a fetus without cardiac structural anomalies. Fetal echocardiography and magnetocardiography were used to diagnose congenital long QT syndrome. It was confirmed in the neonate, and the same pathogenic variant in was subsequently identified in the mother.
PubMed: 38361570
DOI: 10.1016/j.jaccas.2023.102183 -
Clinical Research in Cardiology :... Jun 2024Despite impressive developments in the field of ventricular arrhythmias, there is still a relevant number of patients with ventricular arrhythmias who require... (Review)
Review
Despite impressive developments in the field of ventricular arrhythmias, there is still a relevant number of patients with ventricular arrhythmias who require antiarrhythmic drug therapy and may, e.g., in otherwise drug and/or ablation refractory situations, benefit from agents known for decades, such as mexiletine. Through its capability of blocking fast sodium channels in cardiomyocytes, it has played a minor to moderate antiarrhythmic role throughout the recent decades. Nevertheless, certain patients with structural heart disease suffering from drug-refractory, i.e., mainly amiodarone refractory ventricular arrhythmias, as well as those with selected forms of congenital long QT syndrome (LQTS) may nowadays still benefit from mexiletine. Here, we outline mexiletine's cellular and clinical electrophysiological properties. In addition, the application of mexiletine may be accompanied by various potential side effects, e.g., nausea and tremor, and is limited by several drug-drug interactions. Thus, we shed light on the current therapeutic role of mexiletine for therapy of ventricular arrhythmias and discuss clinically relevant aspects of its indications based on current evidence.
Topics: Mexiletine; Humans; Anti-Arrhythmia Agents; Tachycardia, Ventricular; Treatment Outcome
PubMed: 38353682
DOI: 10.1007/s00392-024-02383-9 -
BioRxiv : the Preprint Server For... Jan 2024The voltage gated potassium ion channel K 11.1 plays a critical role in cardiac repolarization. Genetic variants that render Kv11.1 dysfunctional cause Long QT Syndrome...
INTRODUCTION
The voltage gated potassium ion channel K 11.1 plays a critical role in cardiac repolarization. Genetic variants that render Kv11.1 dysfunctional cause Long QT Syndrome (LQTS), which is associated with fatal arrhythmias. Approximately 90% of LQTS-associated variants cause intracellular protein transport (trafficking) dysfunction, which can be rescued by pharmacological chaperones like E-4031. Protein folding and trafficking decisions are regulated by chaperones, protein quality control factors, and trafficking machinery, comprising the cellular proteostasis network. Here, we test whether trafficking dysfunction is associated with alterations in the proteostasis network of pathogenic Kv11.1 variants, and whether pharmacological chaperones can normalize the proteostasis network of responsive variants.
METHODS
We used affinity-purification coupled with tandem mass tag-based quantitative mass spectrometry to assess protein interaction changes in human embryonic kidney (HEK293) cells expressing wild-type (WT) K 11.1 or trafficking-deficient channel variants in the presence or absence of E-4031.
RESULTSA
We identified 573 core K 11.1 protein interactors. Both variants K 11.1-G601S and K 11.1-G601S-G965* had significantly increased interactions with proteins responsible for folding, trafficking, and degradation compared to WT. We found that proteasomal degradation is a key component for K 11.1 degradation and that the K 11.1-G601S-G965* variant was more responsive to E-4031 treatment. This suggests a role in the C-terminal domain and the ER retention motif of K 11.1 in regulating trafficking.
CONCLUSION
Our report characterizes the proteostasis network of K 11.1, two trafficking deficient K 11.1 variants, and variants treated with a pharmacological chaperone. The identified protein interactions could be targeted therapeutically to improve K 11.1 trafficking and treat Long QT Syndrome.
PubMed: 38352392
DOI: 10.1101/2024.01.31.574410 -
Journal of the American Heart... Feb 2024Although accumulating data indicate that IL-6 (interleukin-6) can promote heart rate-corrected QT interval (QTc) prolongation via direct and indirect effects on cardiac... (Observational Study)
Observational Study
BACKGROUND
Although accumulating data indicate that IL-6 (interleukin-6) can promote heart rate-corrected QT interval (QTc) prolongation via direct and indirect effects on cardiac electrophysiology, current evidence comes from basic investigations and small clinical studies only. Therefore, IL-6 is still largely ignored in the clinical management of long-QT syndrome and related arrhythmias. The aim of this study was to estimate the risk of QTc prolongation associated with elevated IL-6 levels in a large population of unselected subjects.
METHODS AND RESULTS
An observational study using the Veterans Affairs Informatics and Computing Infrastructure was performed. Participants were US veterans who had an ECG and were tested for IL-6. Descriptive statistics and univariate and multivariate regression analyses were performed to study the relationship between IL-6 and QTc prolongation risk. Study population comprised 1085 individuals, 306 showing normal (<5 pg/mL), 376 moderately high (5-25 pg/mL), and 403 high (>25 pg/mL) IL-6 levels. Subjects with elevated IL-6 showed a concentration-dependent increase in the prevalence of QTc prolongation, and those presenting with QTc prolongation exhibited higher circulating IL-6 levels. Stepwise multivariate regression analyses demonstrated that increased IL-6 level was significantly associated with a risk of QTc prolongation up to 2 times the odds of the reference category of QTc (e.g. QTc >470 ms men/480 ms women ms: odds ratio, 2.28 [95% CI, 1.12-4.50] for IL-6 >25 pg/mL) regardless of the underlying cause. Specifically, the mean QTc increase observed in the presence of elevated IL-6 was quantitatively comparable (IL-6 >25 pg/mL:+6.7 ms) to that of major recognized QT-prolonging risk factors, such as hypokalemia and history of myocardial infarction.
CONCLUSIONS
Our data provide evidence that a high circulating IL-6 level is a robust risk factor for QTc prolongation in a large cohort of US veterans, supporting a potentially important arrhythmogenic role for this cytokine in the general population.
Topics: Male; Humans; Female; Interleukin-6; Veterans; Long QT Syndrome; Risk Factors; Arrhythmias, Cardiac; Electrocardiography
PubMed: 38348789
DOI: 10.1161/JAHA.123.032071