Characteristics, predictors and outcomes of new-onset QT prolongation in sepsis: a multicenter retrospective study.

BACKGROUND: Sepsis-induced myocardial injury is a serious complication of sepsis. QT prolongation is a proarrhythmic state which reflects myocardial injury in a group of heterogeneous disorders. However, the study on the clinical value of QT prolongation in sepsis is limited. METHODS: We aimed to investigate the clinical characteristics and predictors of new-onset QT prolongation in sepsis and its impact on the outcome in a multicenter retrospective cohort study. Electrocardiographic and clinical data were collected from patients with sepsis from the wards and intensive care units of four centers after exclusion of QT-influencing medications and electrolyte abnormalities. Clinical outcomes were compared between patients with and without QT prolongation (QTc > 450 ms). Multivariate analysis was performed to ascertain whether QT prolongation was an independent predictor for 30-day mortality. The factors predicting QT prolongation in sepsis were also analyzed. RESULTS: New-onset QT prolongation occurred in 235/1024 (22.9%) patients. The majority demonstrated similar pattern as type 1 long QT syndrome. Patients with QT prolongation had a higher 30-day in-hospital mortality (P < 0.001), which was also associated with increased tachyarrhythmias including paroxysmal atrial fibrillation or tachycardia (P < 0.001) and ventricular arrhythmia (P < 0.001) during hospitalization. QT prolongation independently predicted 30-day mortality (P = 0.044) after multivariate analysis. History of coronary artery disease (P = 0.001), septic shock (P = 0.008), acute respiratory (P < 0.001), heart (P = 0.021) and renal dysfunction (P = 0.013) were independent predictors of QT prolongation in sepsis. CONCLUSIONS: New-onset QT prolongation in sepsis was associated with increased mortality as well as atrial and ventricular arrhythmias, which was predicted by disease severity and organ dysfunction.

Antisense oligonucleotide therapeutic approach for Timothy syndrome.

Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions1. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A2-6. We reasoned that switching CACNA1C exon utilization from 8A to 8 would represent a potential therapeutic strategy. Here we developed antisense oligonucleotides (ASOs) to effectively decrease the inclusion of exon 8A in human cells both in vitro and, following transplantation, in vivo. We discovered that the ASO-mediated switch from exon 8A to 8 robustly rescued defects in patient-derived cortical organoids and migration in forebrain assembloids. Leveraging a transplantation platform previously developed7, we found that a single intrathecal ASO administration rescued calcium changes and in vivo dendrite retraction of patient neurons, suggesting that suppression of CACNA1C exon 8A expression is a potential treatment for TS1. Broadly, these experiments illustrate how a multilevel, in vivo and in vitro stem cell model-based approach can identify strategies to reverse disease-relevant neural pathophysiology.

Virtual clinical QT exposure-response studies - A translational computational approach.

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.

Psychedelic Therapy: A Primer for Primary Care Clinicians-Ibogaine.

BACKGROUND: Ibogaine is a plant-derived alkaloid that has been used for thousands of years in rites of passage and spiritual ceremonies in West-Central Africa. In the West, it has primarily been used and studied for its anti-addictive properties and more recently for other neuropsychiatric indications, including post-traumatic stress disorder, depression, anxiety, and traumatic brain injury. AREAS OF UNCERTAINTY: Ibogaine requires careful patient screening and monitoring because of significant safety issues. There is potential for cardiotoxicity (prolonged QT interval); without rigorous screening, fatal arrhythmias may occur. However, preliminary research suggests that co-administration of ibogaine with magnesium may mitigate cardiotoxicity. Additionally, ibogaine may have dangerous interactions with opiates, so patients who receive ibogaine treatment for opioid use disorder must withdraw from long-acting opioids. Other potential concerning effects of ibogaine include rare incidences of mania or psychosis. Anticipated transient effects during ibogaine treatment can include ataxia, tremors, and gastrointestinal symptoms. THERAPEUTIC ADVANCES: Robust effects after a single treatment with ibogaine have been reported. In open-label and randomized controlled trials (RCTs), ibogaine reduces heroin and opioid cravings by upwards of 50%, up to 24 weeks after the treatment. An observational study of 30 Special Operations Forces veterans with mild traumatic brain injury reported that 86% were in remission from post-traumatic stress disorder, 83% from depression, and 83% from anxiety, one month after a single-dose ibogaine treatment. LIMITATIONS: Although there are several observational and open-label studies, there is only a single double-blind, placebo-controlled RCT on ibogaine. More RCTs with large sample sizes must be conducted to support ibogaine's safety and efficacy. CONCLUSIONS: Given the promising preliminary findings, ibogaine could potentially fill a much-needed gap in treatments for challenging conditions, including opioid dependence. Ibogaine's remarkable effects in traditionally treatment-resistant, combat-exposed individuals hints at its potential in broader populations with physical and psychological trauma.

Methadone for Cancer Pain Management in Children: A Review of Literature.

Pain associated with cancer is a common feature among children and adolescents. Among opioids, methadone is a unique drug for its multiple mechanisms of action. Methadone is currently underutilized in children. The use of methadone for cancer pain management in children was assessed in a systematic review. Altogether, 141 children receiving methadone were examined, and another 126 children were assessed for QT prolongation. In the clinical studies, modalities of use, dosing, and duration of assessment were highly variable. In general, methadone was effective and well tolerated with a limited tendency for dose increases. QT prolongation was reported in a percentage of patients independently of the dosages or other variables. The majority of studies considered the use of methadone to be safe and effective in children. Despite methadone possessing interesting properties that make this drug unique in a pediatric context, data is limited, and the literature available is based on retrospective studies. Methadone could be an effective, inexpensive, and versatile medication in children with cancer who have pain. This drug deserves more interest and should prompt studies of better quality with a larger number of patients.

Repotrectinib in a Patient With NTRK Fusion-Positive Pancreatic Carcinoma and Congenital Long QT Syndrome.

Repotrectinib in a patient with NTRK fusion-positive pancreatic carcinoma and congenital long QT syndrome.

Case report of a child with long QT syndrome type 14 caused by CALM1 gene mutation and literature review.

OBJECTIVE: To analyze the clinical and genetic characteristics of a patient with long QT syndrome type 14 (long QT syndrome-14, LQT14, OMIM # 616247) caused by a de novo CALM1 mutation. METHODS: The clinical data of the patient were collected, next-generation sequencing technology was used to determine the exome gene sequence of the patient, and the suspected pathogenic locus was verified by Sanger sequencing. RESULTS: A 5-year and 9-month-old girl was admitted to the hospital due to a syncopal episode. During the attack, the main symptoms were loss of consciousness, cyanosis of the face and lips, and weakness of limbs. The child had multiple seizures in the past, all of which occurred after emotional excitement and activity. She was diagnosed with epilepsy for more than 3 years, but the effect of antiepileptic treatment was not satisfactory. The electrocardiogram was normal in the past. A month ago, convulsions occurred again after exercise, and the electrocardiogram showed QTc 496 ms. The treadmill test showed a significant prolongation of QTc after exercise, and the genetic results suggested a new heterozygous variant of CALM1, c.395A>G; p. (Asp132Gly). Consequently, she was diagnosed with LQT14 and treated with propranolol. During a follow-up of 15 months, there were no seizures or syncope. CONCLUSIONS: This patient had multiple episodes of convulsions or syncope after emotional stimulation or activity, with intermittent prolongation of the QTc on routine ECG, marked prolongation of the QTc after exercise, and T-wave alternans, which differed from the LQT14 phenotype caused by the previous CALM1 mutation.

Relacorilant, a Selective Glucocorticoid Receptor Modulator in Development for the Treatment of Patients With Cushing Syndrome, Does Not Cause Prolongation of the Cardiac QT Interval.

OBJECTIVE: To assess the effect of relacorilant, a selective glucocorticoid receptor modulator under investigation for the treatment of patients with endogenous hypercortisolism (Cushing syndrome [CS]), on the heart rate-corrected QT interval (QTc). METHODS: Three clinical studies of relacorilant were included: (1) a first-in-human, randomized, placebo-controlled, ascending-dose (up to 500 mg of relacorilant) study in healthy volunteers; (2) a phase 1 placebo- and positive-controlled thorough QTc (TQT) study of 400 and 800 mg of relacorilant in healthy volunteers; and (3) a phase 2, open-label study of up to 400 mg of relacorilant administered daily for up to 16 weeks in patients with CS. Electrocardiogram recordings were taken, and QTc change from baseline (ΔQTc) was calculated. The association of plasma relacorilant concentration with the effect on QTc in healthy volunteers was assessed using linear mixed-effects modeling. RESULTS: Across all studies, no notable changes in the electrocardiogram parameters were observed. At all time points and with all doses of relacorilant, including supratherapeutic doses, ΔQTc was small, generally negative, and, in the placebo-controlled studies, similar to placebo. In the TQT study, placebo-corrected ΔQTc with relacorilant was small and negative, whereas placebo-corrected ΔQTc with moxifloxacin positive control showed rapid QTc prolongation. These results constituted a negative TQT study. The model-estimated slopes of the concentration-QTc relationship were slightly negative, excluding an association of relacorilant with prolonged QTc. CONCLUSION: At all doses studied, relacorilant consistently demonstrated a lack of QTc prolongation in healthy volunteers and patients with CS, including in the TQT study. Ongoing phase 3 studies will help further establish the overall benefit-risk profile of relacorilant.

Type 3 long QT syndrome: Is the effectiveness of treatment with beta-blockers population-specific?

BACKGROUND: The efficacy of beta-blocker treatment in type 3 long QT syndrome (LQT3) remains debated. OBJECTIVES: The purpose of this study was to test the hypothesis that beta-blocker use is associated with cardiac events (CEs) in a French cohort of LQT3 patients. METHODS: All patients with a likely pathogenic/pathogenic variant in the SCN5A gene (linked to LQT3) were included and followed-up. Documented ventricular tachycardia/ventricular fibrillation, torsades de pointes, aborted cardiac arrest, sudden death, and appropriate shocks were considered as severe cardiac events (SCEs). CEs also included syncope. RESULTS: We included 147 patients from 54 families carrying 23 variants. Six of the patients developed symptoms before the age of 1 year and were analyzed separately. The 141 remaining patients (52.5% male; median age at diagnosis 24.0 years) were followed-up for a median of 11 years. The probabilities of a CE and an SCE from birth to the age of 40 were 20.5% and 9.9%, respectively. QTc prolongation (hazard ratio [HR] 1.12 [1.0-1.2]; P = .005]) and proband status (HR 4.07 [1.9-8.9]; P <.001) were independently associated with the occurrence of CEs. Proband status (HR 8.13 [1.7-38.8]; P = .009) was found to be independently associated with SCEs, whereas QTc prolongation (HR 1.11 [1.0-1.3]; P = .108) did not reach statistical significance. The cumulative probability of the age at first CE/SCE was not lower in patients treated with a beta-blocker. CONCLUSION: In agreement with the literature, proband status and lengthened QTc were associated with a higher risk of CEs. Our data do not show a protective effect of beta-blocker treatment.

Assessment of Quinidine-Induced Torsades de Pointes Risks Using a Whole-Body Physiologically Based Pharmacokinetic Model Linked to Cardiac Ionic Current Inhibition.

The lethality of torsades de pointes (TdP) by drugs is one of main reasons that some drugs were withdrawn from the market. In order to assess drug-induced TdP risks, a model of cardiac ionic current suppression in human ventricular myocytes (ToR-ORd model), combined with the maximum effective free therapeutic plasma concentration or the maximum effective free therapeutic myocyte concentration was often used, with the latter proved to be more relevant and more accurate. We aimed to develop a whole-body physiologically-based pharmacokinetic (PBPK) model, incorporated with a human cardiomyocyte pharmacodynamic (PD) model, to provide a comprehensive assessment of drug-induced TdP risks in normal and specific scenarios. Quinidine served as an example to validate the PBPK-PD model via predicting plasma quinidine concentrations and quinidine-induced changes in QT interval (ΔQTc). The predicted plasma quinidine concentrations and ΔQTc values following oral administration or intravenous administration of quinidine were comparable to clinic observations. Visual predictive checks showed that most of the observed plasma concentrations and ΔQTc values fell within the 5th and 95th percentiles of simulations. The validated PBPK-PD model was further applied to assess the TdP risks using frequencies of early afterdepolarization and long-QT syndrome occurrence in 4 scenarios, such as therapeutic dose, supra-therapeutic dose, alkalosis, and hyperkalemia in 200 human subjects. In conclusion, the developed PBPK-PD model may be applied to predict the quinidine pharmacokinetics and quinidine-induced TdP risks in healthy subjects, but also simulate quinidine-induced TdP risks under disease conditions, such as hypokalemia and alkalosis.

Effect of Flecainide and Ibutilide Alone and in Combination to Terminate and Prevent Recurrence of Atrial Fibrillation.

BACKGROUND: There is a need for improved approaches to rhythm control therapy of atrial fibrillation (AF). METHODS: The effectiveness of flecainide (1.5 µmol/L) and ibutilide (20 nmol/L), alone and in combination, to cardiovert and prevent AF recurrence was studied in canine-isolated coronary-perfused right atrioventricular preparations. We also examined the safety of the combination of flecainide (1.5 µmol/L) and ibutilide (50 nmol/L) using canine left ventricular wedge preparations. RESULTS: Sustained AF (>1 hour) was inducible in 100%, 60%, 20%, and 0% of atria in the presence of acetylcholine alone, acetylcholine+ibutilide, acetylcholine+flecainide, and acetylcholine+ibutilide+flecainide, respectively. When used alone, flecainide and ibutilide cardioverted sustained AF in 40% and 20% of atria, respectively, but in 100% of atria when used in combination. Ibutilide prolonged atrial and ventricular effective refractory period by 15% and 8%, respectively, at a cycle length of 500 ms (P<0.05 for both). Flecainide increased the effective refractory period in atria by 27% (P<0.01) but by only 2% in the ventricles. The combination of the 2 drugs lengthened the effective refractory period by 42% in atria (P<0.01) but by only 7% (P<0.05) in the ventricles. In left ventricular wedges, ibutilide prolonged QT and Tpeak-Tend intervals by 25 and 55%, respectively (P<0.05 for both; cycle length, 2000 ms). The addition of flecainide (1.5 µmol/L) partially reversed these effects (P<0.05 for both parameters versus ibutilide alone). Torsades de Pointes score was relatively high with ibutilide alone and low with the drug combination. CONCLUSIONS: In our experimental model, a combination of flecainide and ibutilide significantly improves cardioversion and prevents the recurrence of AF compared with monotherapies with little to no risk for the development of long-QT-mediated ventricular proarrhythmia.

Proof of concept for monoclonal antibody therapy in a cellular model of acquired long QT syndrome type 3.

Long QT syndrome (LQTS) type 3 although less common than the first two forms, differs in that arrhythmic events are less likely triggered by adrenergic stimuli and are more often lethal. Effective pharmacological treatment is challenged by interindividual differences, mutation dependence, and adverse effects, translating into an increased use of invasive measures (implantable cardioverter-defibrillator, sympathetic denervation) in patients with LQTS type 3. Previous studies have demonstrated the therapeutic potential of polyclonal KCNQ1 antibody for LQTS type 2. Here, we sought to identify a monoclonal KCNQ1 antibody that preserves the electrophysiological properties of the polyclonal form. Using hybridoma technology, murine monoclonal antibodies were generated, and patch clamp studies were performed for functional characterization. We identified a monoclonal KCNQ1 antibody able to normalize cardiac action potential duration and to suppress arrhythmias in a pharmacological model of LQTS type 3 using human-induced pluripotent stem cell-derived cardiomyocytes.NEW & NOTEWORTHY Long QT syndrome is a leading cause of sudden cardiac death in the young. Recent research has highlighted KCNQ1 antibody therapy as a new treatment modality for long QT syndrome type 2. Here, we developed a monoclonal KCNQ1 antibody that similarly restores cardiac repolarization. Moreover, the identified monoclonal KCNQ1 antibody suppresses arrhythmias in a cellular model of long QT syndrome type 3, holding promise as a first-in-class antiarrhythmic immunotherapy.

Effects of cohort, genotype, variant, and maternal ß-blocker treatment on foetal heart rate predictors of inherited long QT syndrome.

AIMS: In long QT syndrome (LQTS), primary prevention improves outcome; thus, early identification is key. The most common LQTS phenotype is a foetal heart rate (FHR) < 3rd percentile for gestational age (GA) but the effects of cohort, genotype, variant, and maternal ß-blocker therapy on FHR are unknown. We assessed the influence of these factors on FHR in pregnancies with familial LQTS and developed a FHR/GA threshold for LQTS. METHODS AND RESULTS: In an international cohort of pregnancies in which one parent had LQTS, LQTS genotype, familial variant, and maternal ß-blocker effects on FHR were assessed. We developed a testing algorithm for LQTS using FHR and GA as continuous predictors. Data included 1966 FHRs at 7-42 weeks' GA from 267 pregnancies/164 LQTS families [220 LQTS type 1 (LQT1), 35 LQTS type 2 (LQT2), and 12 LQTS type 3 (LQT3)]. The FHRs were significantly lower in LQT1 and LQT2 but not LQT3 or LQTS negative. The LQT1 variants with non-nonsense and severe function loss (current density or ß-adrenergic response) had lower FHR. Maternal ß-blockers potentiated bradycardia in LQT1 and LQT2 but did not affect FHR in LQTS negative. A FHR/GA threshold predicted LQT1 and LQT2 with 74.9% accuracy, 71% sensitivity, and 81% specificity. CONCLUSION: Genotype, LQT1 variant, and maternal ß-blocker therapy affect FHR. A predictive threshold of FHR/GA significantly improves the accuracy, sensitivity, and specificity for LQT1 and LQT2, above the infant's a priori 50% probability. We speculate this model may be useful in screening for LQTS in perinatal subjects without a known LQTS family history.

Assessment of Severity of Long QT Syndrome Phenotype and Risk of Fetal Death.

BACKGROUND: It has been postulated that long QT syndrome (LQTS) can cause fetal loss through putative adverse effects of the channelopathy on placenta and myometrial function. The authors aimed to describe the fetal death rate in a population of pregnant women with long QT syndrome and investigate whether women with more severe phenotype had worse fetal outcomes. METHODS AND RESULTS: The authors retrospectively evaluated fetal outcomes of 64 pregnancies from 23 women with long QT syndrome followed during pregnancy in a tertiary pregnancy and heart disease program. Thirteen of 64 pregnancies (20%) resulted in a fetal loss, 12 miscarriages (19%), and 1 stillbirth (1.6%). Baseline maternal characteristics, including age and use of ß-blockers, did not differ between women who experienced a fetal death or not. Maternal corrected QT interval (QTc) was significantly longer in pregnancies that resulted in fetal death compared with live births (median, 518 ms [interquartile range (IQR), 482-519 ms] versus 479 ms [IQR, 454-496 ms], P<0.001). Mothers treated with ß-blockers had babies born at term with lower birth weight compared with untreated women (2973±298 g versus 3470±338 g, P=0.002). In addition, the birth weight of babies born at term to treated women with QTc >500 ms was significantly lower compared with women with QTc <500 ms (2783±283 g versus 3084±256 g, P=0.029). CONCLUSIONS: Women with long QT syndrome with more severe phenotypes have a higher incidence of fetal death. Maternal QTc is longer in pregnancies that result in fetal loss, and the birth weight of babies born to patients taking ß-blockers with a QTc >500 ms is lower, suggesting that patients with more marked phenotype may experience worse fetal outcomes.

Cardiac and mortality outcome differences between methadone, buprenorphine and naltrexone prescriptions in patients with an opioid use disorder.

IMPORTANCE: More than 109,000 Americans died of drug overdose in 2022, with 81,231 overdose deaths involving opioids. Methadone, buprenorphine and naltrexone are the most widely used medications for opioid use disorders (MOUD) and the most effective intervention for preventing overdose deaths. However, there is a concern that methadone results in long QT syndrome, which increases the risk for fatal cardiac arrythmias. Currently few studies have systematically evaluated both the short-term and long-term differences in cardiac and mortality outcomes between MOUD. OBJECTIVES: To compare the risks of cardiac arrythmias, long QT syndrome and overall mortality between patients with opioid use disorders (OUD) who were prescribed methadone, buprenorphine or naltrexone. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study based on a multicenter and nationwide database of electronic health records (EHRs) in the United States. The study population was comprised of 144,141 patients who had medical encounters for OUD in 2016-2022, were prescribed MOUD within 1 month following a medical encounter for OUD diagnosis and had no diagnosis of cardiac arrythmias or long QT syndrome before any MOUD prescription. The study population was divided into three cohorts: (1) Methadone cohort (n = 40,938)-who were only prescribed methadone. (2) Buprenorphine cohort (n = 80,055)-who were only prescribed buprenorphine. (3) Naltrexone cohort (n = 5,738)-who were only prescribed naltrexone. EXPOSURES: methadone, buprenorphine, or naltrexone. MAIN OUTCOMES AND MEASURES: Cardiac arrythmias, long QT syndrome, and death. Hazard ratio (HR) and 95% confidence interval (CI) of outcomes at six different follow-up time frames (1-month, 3-month, 6-month, 1-year, 3-year, and 5-year) by comparing propensity-score matched cohorts using Kaplan-Meier survival analysis. RESULTS: Patients with OUD who were prescribed methadone had significantly higher risks of cardiac arrhythmias, long QT syndrome and death compared with propensity-score matched patients with OUD who were prescribed buprenorphine or naltrexone. For the 1-month follow-up, the overall risk for cardiac arrythmias was 1.03% in the Methadone cohort, higher than the 0.87% in the matched Buprenorphine cohort (HR: 1.20, 95% CI: 1.04-1.39); The overall risk for long QT syndrome was 0.35% in the Methadone cohort, higher than the 0.15% in the matched Buprenorphine cohort (HR: 2.40, 95% CI: 1.75-3.28); The overall mortality was 0.59% in the Methadone cohort, higher than the 0.41% in the matched Buprenorphine cohort (HR: 1.48, 95% CI: 1.21-1.81). The increased risk persisted for 5 years: cardiac arrhythmias (HR: 1.31, 95% CI: 1.23-1.38), long QT syndrome (HR: 3.14, 95% CI: 2.76-3.58), death (HR: 1.50, 95% CI: 1.41-1.59). CONCLUSIONS AND RELEVANCE: Methadone was associated with a significantly higher risk for cardiac and mortality outcomes than buprenorphine and naltrexone. These findings are relevant to the development of guidelines for medication selection when initiating MOUD treatment and inform future medication development for OUD that minimizes risks while maximizing benefits.

Autosomal Recessive Long QT Syndrome: Clinical Aspects and Therapy.

The autosomal recessive (AR) form of Long QT Syndrome (LQTS) is described both associated with deafness known as Jervell and Lange-Nielsen (JLN) syndrome, and without deafness (WD). The aim of the study is to report the characteristics of AR LQTS patients and the efficacy of the therapy. Data of all children with AR LQTS referred to the Bambino Gesù Children's Hospital IRCCS from September 2012 to September 2021were included. Three (30%) patients had compound heterozygosity and 7 (70%) had homozygous variants of the KCNQ1 gene, the latter showing deafness. Four patients (40%) presented aborted sudden cardiac death (aSCD): three with previous episodes of syncope (75%), the other without previous symptoms (16.6% of asymptomatic patients). An episode of aSCD occurred in 2/3 (66.7%) of WD and heterozygous patients, while in 2/7 (28%) JLN and homozygous patients and in 2/2 patients with QTC > 600 ms. All patients were treated with Nadolol. In 5 Mexiletine was added, shortening QTc and obtaining the disappearance of the T-wave alternance (TWA) in 3/3. Episodes of aSCD seem to be more frequent in LQTS patients with compound heterozygous variants and WD than in those with JLN and homozygous variants. Episodes of aSCD also appear more frequent in children with syncope or with QTc value > 600 ms, even on beta-blocker therapy, than in patients without syncope or with Qtc < 600 ms. However, our descriptive results should be confirmed by larger studies. Moreover, Mexiletine addition reduced QTc value and eliminated TWA.

Pharmacological Screening of Kv7.1 and Kv7.1/KCNE1 Activators as Potential Antiarrhythmic Drugs in the Zebrafish Heart.

Long QT syndrome (LQTS) can lead to ventricular arrhythmia and sudden cardiac death. The most common congenital cause of LQTS is mutations in the channel subunits generating the cardiac potassium current IKs. Zebrafish (Danio rerio) have been proposed as a powerful system to model human cardiac diseases due to the similar electrical properties of the zebrafish heart and the human heart. We used high-resolution all-optical electrophysiology on ex vivo zebrafish hearts to assess the effects of IKs analogues on the cardiac action potential. We found that chromanol 293B (an IKs inhibitor) prolonged the action potential duration (APD) in the presence of E4031 (an IKr inhibitor applied to drug-induced LQT2), and to a lesser extent, in the absence of E4031. Moreover, we showed that PUFA analogues slightly shortened the APD of the zebrafish heart. However, PUFA analogues failed to reverse the APD prolongation in drug-induced LQT2. However, a more potent IKs activator, ML-277, partially reversed the APD prolongation in drug-induced LQT2 zebrafish hearts. Our results suggest that IKs plays a limited role in ventricular repolarizations in the zebrafish heart under resting conditions, although it plays a more important role when the IKr is compromised, as if the IKs in zebrafish serves as a repolarization reserve as in human hearts. This study shows that potent IKs activators can restore the action potential duration in drug-induced LQT2 in the zebrafish heart.

Comparing the sensitivity of cross-over and parallel study designs for QTc assessment: An analysis based on a single large study of moxifloxacin in 48 nonhuman primates.

The cardiovascular safety pharmacology (SP) study conducted to satisfy ICH S7A and S7B has commonly used a cross-over study design where each animal receives all treatments. In an increasing number of cases, cross-over designs are not possible and parallel studies have to be used. These can seldom be as large as 8 animals/treatment to match an n = 8 cross-over. Animals in parallel designs receive only one treatment. Parallel studies will have a different sensitivity to detect changes. This sensitivity is a critical question in using nonclinical QTc evaluations to support an integrated proarrhythmic risk assessment under the newly released ICH E14/S7B Q&As. The current analysis used a study large enough (n = 48) to be analyzed both as a parallel and as a cross-over design to directly compare the performance of the two experimental designs coupled to different statistical models, while all other study conduct aspects were the same. A total of 48 nonhuman primates (NHP) received 2 different treatments twice: vehicle, moxifloxacin (80 mg/kg), vehicle, moxifloxacin (80 mg/kg). Post-dose QTc interval data were recorded for 48 h for each treatment. Data were analyzed using 12 animals randomly selected for each treatment in a parallel design or as an n = 48 animal cross-over study. Different statistical models were used. The primary endpoint was the residual deviation (sigma) from the models applied to hourly time intervals. The sigma was used to determine the minimal detectable difference (MDD) for the study design-statistical model combination. Two statistical models were applicable to either study design. They gave similar sigma and resulting MDD values. In cross-over designs, the individual animal identification (ID) can be used in the statistical model. This enabled the smallest MDD value. Simple statistical models for analysis were identified: Treatment + Baseline for parallel designs and Treatment + ID for cross-over designs. The statistical sensitivity of NHP parallel study designs is reasonable (MDD for n = 6 of 12.7 ms), and in combination with testing exposures higher than likely to be necessary in man could be used in an integrated risk assessment. Where sensitivity of the NHP in vivo QTc assessment is critical, the cross-over design enabled a higher sensitivity (MDD 12.2 ms for n = 4; 8 ms for n = 8).

Differential Effects of Remdesivir and Lumacaftor on Homomeric and Heteromeric hERG Channels.

The human ether-a-go-go-related gene (hERG) encodes for the pore-forming subunit of the channel that conducts the rapidly activating delayed K+ current (IKr) in the heart. The hERG channel is important for cardiac repolarization, and reduction of its expression in the plasma membrane due to mutations causes long QT syndrome type 2 (LQT2). As such, promoting hERG membrane expression is a strategy to rescue mutant channel function. In the present study, we applied patch clamp, western blots, immunocytochemistry, and quantitative reverse transcription polymerase chain reaction techniques to investigate the rescue effects of two drugs, remdesivir and lumacaftor, on trafficking-defective mutant hERG channels. As our group has recently reported that the antiviral drug remdesivir increases wild-type (WT) hERG current and surface expression, we studied the effects of remdesivir on trafficking-defective LQT2-causing hERG mutants G601S and R582C expressed in HEK293 cells. We also investigated the effects of lumacaftor, a drug used to treat cystic fibrosis, that promotes CFTR protein trafficking and has been shown to rescue membrane expression of some hERG mutations. Our results show that neither remdesivir nor lumacaftor rescued the current or cell-surface expression of homomeric mutants G601S and R582C. However, remdesivir decreased while lumacaftor increased the current and cell-surface expression of heteromeric channels formed by WT hERG and mutant G601S or R582C hERG. We concluded that drugs can differentially affect homomeric WT and heteromeric WT+G601S (or WT+R582C) hERG channels. These findings extend our understanding of drug-channel interaction and may have clinical implications for patients with hERG mutations. SIGNIFICANCE STATEMENT: Various naturally occurring mutations in a cardiac potassium channel called hERG can impair channel function by decreasing cell-surface channel expression, resulting in cardiac electrical disturbances and even sudden cardiac death. Promotion of cell-surface expression of mutant hERG channels represents a strategy to rescue channel function. This work demonstrates that drugs such as remdesivir and lumacaftor can differently affect homomeric and heteromeric mutant hERG channels, which have biological and clinical implications.