QTc Changes Research Articles

Demonstrating the statistical and pharmacological sensitivity of nonclinical QTc analysis using a dofetilide dose-response in nonhuman primates.

Nonclinical QTc studies can augment clinical QTc assessments in regulatory submissions provided they are of sufficient quality and sensitivity. Both the statistical performance and species translation play a role in determining the sensitivity of the model. The current analyses examine the effects of dofetilide or vehicle on the QT interval in nonhuman primate (NHP; n=16) using a one-step estimated marginal means method where both treatment and animal ID are used in regression models to avoid a separate rate correction step, in comparison to other commonly utilized methods. The doses of dofetilide were chosen to span a threshold dose with exposure only just exceeding the concentration associated with 10ms QTc prolongation in man, to a dose where exposures exceed the Emax for QTc prolongation. The primary objective was an evaluation of which doses and exposures can be detected as eliciting a statistically significant change in QTc. A group size of 8 for cross-over analysis was insufficient to detect, as statistically significant, the effects of the threshold dose of 0.01mg/kg dofetilide using common correction and statistical analysis methods and hourly time intervals. Higher doses were all detected as causing a statistically significant effect using the same techniques. The 'One-Step' method was able to detect as statistically significant effects at all doses of dofetilide across a wide range of time and exposure. There were also temporal differences between the mean effects observed using the common and 'One-Step' methods. Preliminary concentration-QTc assessment suggests a higher maximum prolongation in concentration QTc with the 'One-Step' method. Furthermore, this analysis suggests that at exposures associated with a 10ms QTc prolongation in man a 10ms prolongation is also observed in NHP. The observed ED50 concentration (0.85ng/ml unbound) is close to that described in man (0.98ng/ml). These analyses demonstrate the statistical sensitivity of the 'One-Step' method of QTc assessment in NHP. The pharmacological sensitivity was also demonstrated and a detection threshold of 10ms was consistent in terms of exposure between NHP and man. Overall, QTc assessment using the 'One-Step' method in NHP is a robust and sensitive model to supplement clinical QTc assessment.

Investigating the effects of remdesivir on corrected QT interval in patients with severe COVID-19 disease: a historical cohort study

BackgroundThere is little information about the risk of drug-induced QT prolongation by remdesivir as the most important FDA approved anti COVID-19 drug. Prolongation of corrected QT interval (QTc) is considered as an indicator of an unfavorable outcome which may ultimately induce torsade de pointes and provoke ventricular fibrillation. The aim of this study was to determine the effects of remdesivir on QTc in patients with severe COVID 19 disease.MethodsA historical cohort study was conducted on 249 patients who experienced severe COVID-19 disease and were candidate for treatment by intravenous remdesivir. We obtained a 12 lead electrocardiogram at the admission time and five days later to find any significant change in QTc and QT interval following therapy. We took blood samples at the time of hospitalization and then every day to determine the serum levels of electrolytes, complete blood count, fasting blood sugar (FBS), creatinine (Cr), and complete blood count.ResultsThe results of this analysis showed blood pressure and heart rate (HR) were lower and total white blood cells and neutrophil counts, FBS and Cr levels were higher at fifth day than first day of study (P value < 0.001). Furthermore, QT interval was more prolonged at fifth day compared with beginning of remdesivir therapy (379.51 ± 34.90ms vs. 366.72 ± 30.97ms, P value < 0.001). However, QTc was not significantly increased at fifth day in comparison with first day (402.37 ± 33.62ms vs. 400.76 ± 30.18ms, P value = 0.524 by Bazett’s formula and 402.81 ± 36.33 vs. 400.78 ± 32.49, P value = 0.459 by Fridericia’s formula).ConclusionsThe current study found no evidence linking the administration of remdesivir with prolongation of the QTc interval.

Abstract 4135211: Children with the D801N Variant of the ATP1A3- Encoded Sodium-Potassium ATPase Alpha-3 Subunit Demonstrate Paradoxical QT Response to Bradycardia and Increased Ventricular Arrhythmia Risk

Introduction: Alternating hemiplegia of childhood (AHC) is a rare condition most frequently caused by mutations in ATP1A3, encoding for the alpha-3 subunit of Na + /K + -ATPase, and D801N is the most common variant. Individuals with ATP1A3-D801N have shorter corrected QT (QTc) than those with other variants and can experience ventricular arrhythmias following bradycardia; however, the mechanism of why this occurs is unknown. Goals: To analyze how QT and QTc change with heart rate in ATP1A3-D801N compared to healthy individuals. Hypothesis: Individuals with ATP1A3-D801N have increased shortening of QT and QTc at lower heart rate. Methods: In this retrospective observational study, patients seen for evaluation of AHC at Duke University Medical Center were categorized by genotype: ATP1A3-D801N, ATP1A3 non-D801N single nucleotide variant, ATP1A3 loss-of-function variant, and genotype negative. A cohort of matched healthy children was also compiled. We collected average heart rate, QT, and QTc measurements over 5-minute intervals from Holter recordings using HScribe TM software and conducted manual blinded validation to ensure accuracy. We then used linear regression to investigate the relationship between heart rate, QT, and QTc. Results: The cohort consisted of 44 patients with ATP1A3 -related phenotypes with 81 total Holter recordings (52.27% female; mean age at first Holter 8.04 years), compared to 36 healthy individuals with 57 total Holter recordings (52.78% female; mean age at first Holter 9.84 years). Patients with ATP1A3-D801N showed diminished prolongation of QT with decreasing heart rate, manifested as a reduced mean slope for heart rate vs QT compared to healthy (-0.85 ± 0.46 vs -1.52 ± 0.42, p&lt;0.0001). This blunted QT response resulted in paradoxical shortening of QTc at lower heart rate, demonstrated by an increased mean slope for heart rate vs QTc compared to healthy (0.80 ± 0.51 vs 0.22 ± 0.43, p&lt;0.0001). Further, patients with ATP1A3- related phenotypes and very short baseline QTc showed increased shortening of QT and QTc at lower heart rate compared to those with normal QTc (p=0.0025 and p=0.0013, respectively). Conclusions: Children with AHC and ATP1A3-D801N demonstrate a paradoxical shortening of QT and QTc with slowing of heart rate. The impaired prolongation of QT and resultant further shortening of QTc increase the risk of arrhythmia. We put this forward as a novel mechanism of sudden cardiac arrest in patients with ATP1A3 mutations.

Intraoperative Methadone in Adult Cardiac Surgical Patients and Risks for Postoperative QTc Prolongation

To evaluate the effect of intraoperative intravenous methadone within a standardized enhanced recovery after cardiac surgery pathway on the perioperative corrected QT interval (QTc). Retrospective cohort study. Cardiac surgical patients from a tertiary academic medical institution. Eligible 1,040 adult patients undergoing elective cardiac surgery from July 2020 through July 2023 using validated institutional electronic medical record data INTERVENTIONS: Patients were administered intravenous methadone (0.1 mg/kg) or received analgesics other than intravenous methadone as part of an enhanced recovery after cardiac surgery pathway. The primary outcomes were change in QTc and the percent QTc change between preoperative QTc and postoperative QTc upon intensive care unit admission. Secondary outcomes include postoperative ventricular arrhythmias, postoperative atrial fibrillation, intensive care unit length of stay, 30-day mortality, 1-year mortality, and mortality days from surgery. Out of a total of 1,040 patients, 423 received intraoperative methadone and 617 did not receive methadone. Methadone QTc mixed models demonstrated that QTc is prolonged immediately postoperatively and normalized 24 hours after surgery in both methadone and nonmethadone groups. There were no significant differences in baseline QTc, immediate postoperative QTc, changes in QTc, or percent change in QTc between the methadone and nonmethadone groups. There were no significant differences in ventricular or atrial arrhythmias, 30-day mortality, 1-year mortality, or days to death. A single intraoperative intravenous methadone dose did not prolong the QTc significantly or increase the incidence of arrhythmias and may be safe in adult cardiac surgical patients.

Dynamic QTc interval changes observed in real-world patients with implanted insertable cardiac monitors taking class III antiarrhythmic drugs

Abstract Background QT prolongation can lead to sustained ventricular arrhythmias . Class III Antiarrhythmic drugs (AAD) are known to cause QT prolongation. Insertable cardiac monitors (ICM) have the capability to continuously monitor and detect dynamic changes in QT. Purpose To investigate the characteristics of QTc interval changes before and after antiarrhythmic drug loading in real-world ICM patients administered with Sotalol, Amiodarone, and Dofetilide in hospital. Methods The QT detection algorithm detects the T-waves and determines the QTc intervals for every beat, thus providing continuous long-term QTc trends from ICM ECG. Real-world patients from de-identified Electronic Health Record (EHR) database linked with ICM device data warehouse with implanted ICM being administered sotalol, amiodarone or dofetilide AAD for the first time in the hospital were analyzed. The patients were broken down into groups based on the AAD taken. Patients not taking AAD were selected as control. QTc intervals 7-days pre and post administered AAD are reported, and a random 14-day period was used for control patients. The paired difference in median QTc 7 days pre and post administered AAD were analyzed using the Wilcoxon signed rank test. The Wilcoxon rank-sum test was used to analyze QTc between the different groups. Results A total of 487 patients with ICM were included in this analysis: 56 sotalol patients (avg. age: 67±10 years, 50% male), 100 amiodarone patients (avg. age: 72±10 years, 50% male), 52 dofetilide patients (avg. age: 66±12 years, 50% male), and 248 control patients (avg. age: 70±13 years, 50% male). Sotalol, amiodarone, and dofetilide patients showed significant increase in QTc 1-7 days post AAD compared to 1-7 days pre AAD (figure 1). For sotalol (post AAD median[IQR] = 426.5[408.8,446.6] msec, pre AAD median[IQR] = 415.9[391,437.3] msec, p=0.004); Dofetilide (post median[IQR] = 432.4[413,458.7] msec; pre median[IQR] = 409.3[397.5,435.2] msec, p&amp;lt;0.001); Amiodarone (post median[IQR] = 426.3[400.9,449] msec, pre median[IQR] = 415.5[397.5,435.2] msec, p = 0.037). The QTc 1-7 days pre AAD compared to 1-7 days post AAD for control patients was insignificant p&amp;gt;0.05. The median change in QTc 1-7 days post AAD from 1-7 days pre AAD was 13.0, 7.5, 21.25 and -1.0 msec for sotalol, amiodarone, dofetilide, and control patients respectively (figure 2). Dofetilide patients had a significantly higher change in QTc compared to the amiodarone patients, p=0.018. QTc for all three AAD groups when compared to control group post AAD were significantly higher, p&amp;lt;0.001. QTc was also higher pre AAD compared to control, p=0.003, p&amp;lt;0.001, p=0.009 for sotalol, amiodarone, and dofetilide respectively. Conclusions There is a significant increase in QTc detected by ICM in patients receiving index drug loading of Sotalol, amiodarone and dofetilide. QTc monitoring via ICM can detect these dynamic changes in QTc allowing for early intervention.Figure 1Figure 2

Safety of single-dose bedaquiline combined with rifampicin for leprosy post-exposure prophylaxis: A Phase 2 randomized non-inferiority trial in the Comoros Islands.

To reduce leprosy risk in contacts of patients with leprosy by around 50%, the World Health Organization (WHO) recommends leprosy post-exposure prophylaxis (PEP) using single-dose rifampicin (SDR). Results from a cluster randomized trial in the Comoros and Madagascar suggest that PEP with a double dose of rifampicin led to a similar reduction in incident leprosy, prompting the need for stronger PEP. The objective of this Phase 2 trial was to assess safety of a bedaquiline-enhanced PEP regimen (intervention arm, bedaquiline 800 mg with rifampicin 600 mg, BE-PEP), relative to the WHO recommended PEP with rifampicin 600 mg alone (control arm, SDR-PEP). From July 2022 to January 2023, consenting participants were screened for eligibility, including a heart rate-corrected QT interval (QTc) <450 ms and liver enzyme tests (ALT/AST) below 3× the upper limit of normal (ULN), before they were individually randomized 1:1 in an open-label design. Recruitment was sequential, by age group. Pediatric dosages were weight adjusted. Follow-up was done at day 1 post-dose (including ECG) and day 14 (including ALT/AST), with repeat of ALT/AST on the last follow-up at day 30 in case of elevation on day 14. The primary outcome was non-inferiority of BE-PEP based on a <10 ms difference in QTc 24 h after treatment administration, both unadjusted and adjusted for baseline QTc. Of 408 screened participants, 313 were enrolled, starting with 187 adults, then 38 children aged 13 to 17 years, and finally 88 children aged 5 to 12 years, of whom 310 (99%) completed all visits. Across all ages, the mean QTc change on BE-PEP was from 393 ms to 396 ms, not significantly different from the change from 392 ms to 394 ms on SDR-PEP (difference between arms 1.8 ms, 95% CI -1.8, 5.3, p = 0.41). No individual's QTc increased by >50 ms or exceeded 450 ms after PEP administration. Per protocol, all children were analyzed together, with no significant difference in mean QTc increase for BE-PEP compared to SDR-PEP, although non-inferiority of BE-PEP in children was not demonstrated in unadjusted analysis, as the upper limit of the 95% CI of 10.4 ms exceeded the predefined margin of 10 ms. Adjusting for baseline QTc, the regression coefficient and 95% CI (3.3; -1.4, 8.0) met the 10 ms non-inferiority margin. No significant differences in ALT or AST levels were noted between the intervention and control arms, although a limitation of the study was false elevation of ALT/AST during adult recruitment due to a technical error. In both study arms, one serious adverse event was reported, both considered unlikely related to the study drugs. Dizziness, nausea, headache, and diarrhea among adults, and headaches in children, were nonsignificantly more frequently observed in the BE-PEP group. In this study, we observed that safety of single-dose bedaquiline 800 mg in combination with rifampicin is comparable to rifampicin alone, although non-inferiority of QTc changes was demonstrated in children only after adjusting for the baseline QTc measurements. A Phase 3 cluster randomized efficacy trial is currently ongoing in the Comoros. ClinicalTrials.gov NCT05406479.

Olanzapine Versus Quetiapine: Corrected QT Changes in Critically Ill Patients.

Olanzapine and quetiapine are frequently administered atypical antipsychotic medications and their effects on the corrected QT (QTc) in the critically ill population remain understudied. The objective of this study was to compare the impact of olanzapine and quetiapine on QTc changes in critically ill patients. This was a single-center, retrospective analysis. Adult patients admitted to the intensive care unit (ICU) from January 2023 through July 2023 were included if they received ≥2 doses of either olanzapine or quetiapine within a 48-hour period and had one QTc evaluated within 48 hours of antipsychotic initiation. The major endpoint was a composite of the incidence of QTc prolongation (defined as QTc > 500 ms or QTc > 60 ms above baseline) following antipsychotic initiation. Univariable and multivariable analyses were performed to identify risk factors for QTc prolongation. There was no statistical difference in the major composite endpoint between patients in the olanzapine and quetiapine groups (8/83 [9.6%] vs 19/129 [14.7%]; P = .28). The incidence of QTc > 500 ms (7/244 [2.9%] vs 20/427 [4.7%]; P = .25) and change from baseline >60 ms (5/244 [2.0%] vs 17/427 [4.0%]; P = .26) were not statistically different between the olanzapine and quetiapine groups, respectively. There were no occurrences of Torsades de Pointes or extrapyramidal symptoms in either group. The results of this study suggest olanzapine and quetiapine may have similar impact on QTc prolongation in critically ill patients. These findings could contribute to safer prescribing practices in the ICU.

QTc Interval Prolongation as an Adverse Event of Azole Antifungal Drugs: Case Report and Literature Review.

QTc prolongation and torsade de pointes (TdP) are significant adverse events linked to azole antifungals. Reports on QTc interval prolongation caused by these agents are limited. In this study, we report a case of a 77-year-old male with cardiovascular disease who experienced QTc prolongation and subsequent TdP while being treated with fluconazole for Candida albicans-induced knee arthritis. Additionally, a literature review was conducted on cases where QTc prolongation and TdP were triggered as adverse events of azole antifungal drugs. The case study detailed the patient's experience, whereas the literature review analyzed cases from May 1997 to February 2023, focusing on patient demographics, underlying diseases, antifungal regimens, concurrent medications, QTc changes, and outcomes. The review identified 16 cases, mainly in younger individuals (median age of 29) and women (75%). Fluconazole (63%) and voriconazole (37%) were the most common agents. Concurrent medications were present in 75% of cases, and TdP occurred in 81%. Management typically involved discontinuing or switching antifungals and correcting electrolytes, with all patients surviving. Risk assessment and concurrent medication review are essential before starting azole therapy. High-risk patients require careful electrocardiogram monitoring to prevent arrhythmias. Remote monitoring may enhance safety for patients with implanted devices. Further studies are needed to understand risk factors and management strategies.

Effect of long-term use of antipsychotics on the ventricular repolarization index

BackgroundThe risk of arrhythmia is usually assessed by the length of the corrected QT interval (QTc) when patients use antipsychotics. Prolonged QTc intervals are thought to increase the probability of malignant ventricular arrhythmias, and if we focus only on the QTc interval, we may be influenced by a single factor and make decisions that are not conducive to effective treatment. The index of cardiac electrophysiological balance (iCEB) is considered more valuable than the QTc for predicting drug-induced arrhythmias. It has been used in clinical practice, but no studies have observed changes in this index after the use of antipsychotics.ObjectiveTo investigate the changes in ventricular repolarization indices and the occurrence of arrhythmias in patients who have been using antipsychotic drugs for a long time, to compare the changes in iCEBc and QTc and to predict abnormal iCEBc values.MethodsPatients with schizophrenia who had been hospitalized for more than 4 years and who were receiving atypical antipsychotics underwent a 12-lead synchronized electrocardiogram (ECG) every 2–4 weeks. The baseline data were measured at admission, defined as the baseline (time0), and the most obvious abnormal changes in ventricular depolarization and repolarization measured every 12 months were one-year follow-up (time1), two-year follow-up (time2), three-year follow-up (time3), and four-year follow-up (time4). Repeated measures analysis of variance was used for comparisons. The types and doses of drugs taken at 5 time points were recorded and converted into chlorpromazine equivalents for comparison. The incidence of arrhythmia during the observation cycle was recorded.ResultsThe patients had been treated with antipsychotic medication for 4 years, and the duration of the QRS wave was longer in males than in females. TpTe, TpTe/QRS, TpTe/QT, TpTe/QTc, iCEB, and iCEBc increased significantly with hospital stay, while TpTe, TpTe/QRS, TpTe/QT, and TpTe/QTc exhibited more obvious changes in these indicators in female patients (P < 0.01). The changes in iCEB and iCEBc were more significant in males (P < 0.01). The incidences of arrhythmia (arrhythmic events included premature ventricular beats and premature atrial beats) within 5 time points were 2.5%, 6.25%, 6.25%, 6.25% and 5%, respectively. More than 90% of patients treated with antipsychotics did not have any arrhythmias. No TdP syncope or other cardiovascular symptoms were found in any of the patients.ConclusionAfter long-term use of antipsychotics, the ventricular repolarization index gradually increased with time. The new ventricular repolarization indices iCEB and iCEBc were more sensitive than the QTc at predicting arrhythmia. According to the abnormal QTc values in men and women, we predict that the abnormal value of the iCEBc in males is 4.528 and that in females is 5.315.

A simple accurate method for concentration-QTc analysis in preclinical animal models

In preclinical cardiovascular safety pharmacology studies, statistical analysis of the rate corrected QT interval (QTc) is the focus for predicting QTc interval changes in the clinic. Modeling of a concentration/QTc relationship, common clinically, is limited due to minimal pharmacokinetic (PK) data in nonclinical testing. It is possible, however, to relate the average drug plasma concentration from sparse PK samples over specific times to the mean corrected QTc. We hypothesize that averaging drug plasma concentration and the QTc-rate relationship over time provides a simple, accurate concentration-QTc relationship bridging statistical and concentration/QTc modeling. Cardiovascular telemetry studies were conducted in non-human primates (NHP; n=48) and canines (n=8). Pharmacokinetic samples were collected on separate study days in both species. Average plasma concentrations for specific intervals (CAverage0-X) were calculated for moxifloxacin in canines and NHP using times corresponding to super-intervals for the QTc data statistical analysis. The QTc effect was calculated for each super-interval using a linear regression correction incorporating QT and HR data from the whole super-interval. The concentration QTc effects were then modeled. In NHP, a 10.9±0.06ms (mean±95% CI) change in QTc was detected at approximately 1.5× the moxifloxacin plasma concentration that causes a 10ms QTc change in humans, based on a 0-24h super-interval. When simulating a drug without QT effects, mock, no effect on QTc was detected at up to 3× the clinical concentration. Similarly, in canines, a 16.6±0.1ms change was detected at 1.7× critical clinical moxifloxacin concentration, and a 0.04±0.1ms change was seen for mock. While simultaneous PK and QTc data points are preferred, practical constraints and the need for QTc averaging did not prevent concentration-QTc analyses. Utilizing a 0-24h super-interval method illustrates a simple and effective method to address cardiovascular questions when preclinical drug exposures exceed clinical concentrations.

Interplay of electrical and mechanical properties in transgenic rabbit models of long-QT and short-QT syndrome

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): SNF Introduction Long-QT syndrome (LQTS) and short-QT syndrome (SQTS) are cardiac disorders primarily affecting electrical function but secondarily also impacting on mechanical features through electro-mechanical coupling (EMC). This study delves into in vivo and cellular electro-mechanical function and explores the impact of acute mechanical changes on the electrical phenotype, termed mechano-electrical coupling (MEC), in transgenic rabbit models. Aim This study aims to investigate the interrelationship between electrical and mechanical properties in LQTS and SQTS rabbit models, examining how acute mechanical alterations influence the electrical phenotype and exploring cellular electro-mechanical characteristics. Methods We examined 12-lead ECGs in LQT2, wildtype (WT), and SQT1 adult rabbits under various preload and afterload conditions. Additionally, patch-clamp and ionoptix experiments on isolated ventricular cardiomyocytes were conducted to investigate cellular electrical and mechanical characteristics. Results Baseline heart-rate corrected QTc intervals were prolonged in LQT2 (p&amp;lt;0.0001) and shortened in SQT1 (p=0.012) compared to WT. QT-dispersion was solely increased in LQT2 (p&amp;lt;0.05). Acute increase in preload and in afterload prolonged QTc intervals in all groups, while reduced preload shortened QTc intervals. MEC (mechano-induced ΔQTc) varied among genotypes; in LQT2, QTc changes were more significant than in WT (p&amp;lt;0.0001 with increased preload, p&amp;lt;0.001 with decreased preload, and p&amp;lt;0.05 with increased afterload). SQT1 showed a trend towards less pronounced changes compared to WT only after increased preload (p=0.11). At the cellular level, action potential duration was longer in LQT2 (p&amp;lt;0.001) and shorter in SQT1 (p&amp;lt;0.0001) compared to WT. While cardiomyocytes from WT and SQT1 showed similar Ca2+ transient durations at 1Hz, 0.5Hz, and 0.25Hz, in LQT2 cardiomyocytes Ca2+ transients were significantly prolonged at 0.5 (p&amp;lt;0.001) and 0.25Hz (p&amp;lt;0.05) in line with the pronounced APD prolongation. Additionally, LQT2 exhibited significantly more pro-arrhythmic Ca2+ oscillations, which may contribute to arrhythmia formation in LQT2s. Moreover, LQT2 exhibited a slower calcium transient upstroke velocity and a reduced cellular contraction velocity and peak sarcomere shortening at all frequencies, demonstrating a mechanical impairment compared to WT and SQTS cardiomyocytes. Conclusions Acute mechanical alterations induce electrical changes through MEC in LQT2, WT, SQT1 rabbits. The magnitude of these changes correlates with baseline QTc, exhibiting the most prominent effects in LQT2. Consistent findings between cellular electro-mechanical assessments and in vivo measurements underscore the significance of cardiomyocytes in unravelling the mechanisms behind EMC and MEC. This intricate interplay between electro-mechanical properties in cardiac disorders, highlighting the necessity of considering both aspects when investigating arrhythmia mechanisms.

The effect of antipsychotic medications on QTc and delirium in paediatric cardiac patients with ICU delirium.

Children with prolonged hospital admissions for CHD often develop delirium. Antipsychotic medications (APMs) have been used to treat delirium but are known to prolong the QTc duration. There is concern for prolongation of the QTc interval in cardiac patients who may be more vulnerable to electrocardiogram (ECG) changes and may have postoperative QTc prolongation already. The goal of this study was to determine the effect of APM on QTc duration in postoperative paediatric cardiac patients and determine the effect of quetiapine and risperidone in treating delirium and QTc prolongation. Retrospective study, July 1, 2017-May 31, 2022. Tertiary children's hospital. Included were patients admitted to the paediatric cardiac ICU at Children's Healthcare of Atlanta. None. ECGs, delirium scores, and drug information were collected. Delirium was defined as Cornell Assessment of Pediatric Delirium (CAPD) score >9. Mixed effect models were performed to evaluate the effect of surgery on QTc change and the effect of antipsychotics on QTc and CAPD changes. There were 139 children, 55% male and 67% surgical admissions. Median age was 5.9 months. Mean QTc increased after cardiac surgery by 18 ms (p = 0.014, 95% CI 3.65-32.4). There was no significant change in QTc after antipsychotic administration (p = 0.064). The mean CAPD score decreased (12.5-7.2; p < 0.001). Quetiapine had the most improvement in delirium, and risperidone had the least improvement (77.8%, n = 14; 37.8%, n = 34, respectively; p = 0.002). The QTc interval did not have a statistically significant change after the administration of antipsychotics, while there was improvement in the CAPD score. APMs may be administered safely without significant prolongation of the QTc and are an effective treatment for delirium.

Continuous QT interval monitoring using insertable cardiac monitors during antiarrhythmic loading hospitalization: Results from the "LINQ QT" Study

Abstract Background QT interval prolongation is associated with the development of potentially lethal cardiac arrhythmias. An implantable cardiac monitor (ICM) capable of longitudinal QT monitoring may allow for mobile assessment of dynamic changes in QT and assist in predicting long term cardiotoxicity. Objective Determine feasibility of continuous QTc interval monitoring in patients with ICM hospitalized for antiarrhythmic drug loading. Methods The previously described QT detection algorithm for an ICM determines the QT interval for every beat thus providing continuous long-term QT trends. QT intervals detected from continuously collected ICM ECG data from patients enrolled in a prospective clinical study from three sites was analyzed with the primary objective of studying the long-term QT interval trends in patients undergoing antiarrhythmic drug loading in an inpatient setting. The ICM ECG was processed through the QT detection algorithm which calculates the QTc interval for every beat to generate continuous long term QTc trends. Metrics including mean and median QTc, minimum and maximum QTc, and magnitude of QTc change were studied during the hospitalization period. Continuous QTc interval trend is presented from a patient displaying increase in QTc interval following antiarrhythmic drug loading during the hospitalization period. Results 5 out of 17 patients enrolled (avg. age 71±7.3 years, 40% females) in the QT clinical study had continuous telemetered ICM ECG data available during the index antiarrhythmic loading hospitalization period. All patients were loaded with Sotalol during the hospitalization. All 5 patients had hypertension and atrial fibrillation (AF). 3 patients (60%) had a history of myocardial infarction (MI), congestive heart failure (CHF), and coronary artery disease (CAD) while 1 patient (20%) had diabetes. The magnitude of change in QTc over the hospitalization period was 139±42 msec with over 100 msec QTc change noticed in 4 of 5 patients (80%) (figure 1). Figure 2 shows continuous QTc interval trend observed from a patient (Male; Age:75; history of AF, hypertension, CHF, stroke) from this study showing a continuous increase in QTc interval. Overall, there was over 150 msec change in QTc observed for this patient during the hospitalization period. Premature ventricular complexes (PVCs) in a pattern of bigeminy were observed from ICM ECG for a 3-hr period from 12 pm-3 pm following the second antiarrhythmic dose which coupled with QT prolongation could indicate early signs of cardiotoxicity (figure 2). The five static 12-lead ECG measurements taken for this patient during the hospitalization period is also reported with the difference between these 12-lead QTc measurements and algorithm measured QTc being 22±8 msec. Conclusion ICM QT monitoring performed utilizing a QT interval detection algorithm can provide longitudinal and long-term dynamic QT trends in patients implanted with ICM.

#570 A study of QTc time trends and factors affecting QTc changes during dialysis

Abstract Background and Aims Several studies have revealed the relationship between an abnormal QTc interval and mortality with sudden death in patients undergoing haemodialysis (HD). The QTc interval in HD is regulated by several factors, such as electrolytes, pH, and drugs. However, few studies have investigated the changes in the QTc interval during HD sessions and the determining factors. Therefore, we investigated the relationship between changes in electrolytes and QTc interval during HD. Method In this cross-sectional study, 53 patients undergoing maintenance HD were enrolled. Electrocardiogram and blood samples were obtained two days after dialysis. QTc was measured every hour from the start of the HD session, and blood samples were collected at the start, 2 h after, and at the end of the HD session. At the start of the HD session, we measured the blood levels of urea nitrogen, creatinine, β2-microglobulin (β2MG), HCO3-, albumin, intact-parathyroid hormone, phosphorus, Ca, Mg, and K. Blood Ca, Mg, K, and HCO3- levels were evaluated at the start, 2 h after, and at the end of the HD session. The relationship between changes in the QTc interval and various parameters was analysed by Spearman correlation analysis and multiple regression analysis. Results The patients were aged 37–91 (median; 71.5) years, and the duration of dialysis was 1–402 months (median; 2 months). Of the patients, 40.4% were diagnosed as the prolonged QTc interval (≥460 ms) at the start of HD (median; 455 ms). Conversely, 15.9% of patients at 2 h after the start of HD (median; 444 ms) and 8.4% of patients at end of HD (447 ms) were normalized in QTc interval. The peak change in the QTc interval occurred 2 h after start of HD. Thus, we estimated the factors that affected the change in QTc 2 h after the start of dialysis (ΔQTc2h). The duration of HD treatment (r = 0.312, P = 0.025) and serum levels of β2MG (r = 0.324, P = 0.019) were positively correlated with ΔQTc2h. The 2-h change in corrected Ca (ΔcCa2h) (r = −0. 31, P = 0.03) and intact-PTH (r = −0.30, P = 0.035) were negatively correlated with ΔQTc2h. We found no significant correlation between ΔQTc2h and changes in K and Mg. According to the multiple regression analysis, ΔcCa2h (β = −0.293, P = 0.033) and β2MG (β = 0.271, P = 0.042) were significant predictors of ΔQTc2h. Conclusion We anticipated that QTc interval might be prolonged due to the decreased serum K and Mg levels via HD treatments. However, QTc levels during HD were shortened according to increased serum Ca levels. Among the electrolyte levels, the change in blood Ca was significantly correlated with the change in the QTc interval but not with the change in Mg and K. The study results suggest the importance of optimal dialysate electrolytes composition to prevent adverse events and premature death caused by abnormalities in the QTc interval.

Assessment of Repeated Electrocardiogram Findings in Pediatric Multisystem Inflammatory Syndrome Associated with COVID-19

Background: Cardiac involvement, stemming from the novel multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease-2019 (COVID-19), leads to common and severe complications. Objectives: The aim of this study is to compare and evaluate repetitive electrocardiogram (ECG) results and laboratory indicators in children diagnosed with MIS-C upon their initial hospital admission. Methods: This prospective, single-center study, conducted between December 2020 and October 2022, included repeated electrocardiographic and laboratory tests. Changes in the ECG over the course of the disease were regularly recorded for three months. Results: This study included 72 patients, 25 of whom were female. Mitral regurgitation and left ventricular systolic dysfunction were observed in 25% of the patients. Statistically significant differences (P &lt; 0.05) were detected among the serial measurements of absolute neutrophil-lymphocyte count, CRP, procalcitonin, ESR, D-dimer, troponin T, pro-BNP, ferritin, and interleukin-6. Significant differences were also observed in heart rate, PR interval, QRS duration, QT duration, Fredericia QTc, JT interval, presence of sinus tachycardia, presence of first-degree AV block, presence of wide QRS, abnormal QRS axis, abnormal T axis, long QTc, and ST-T changes (P &lt; 0.05). Additionally, significant differences were noted in the absolute lymphocyte count, troponin levels, and ferritin levels between patients with prolonged abnormal ECG findings and those whose ECG findings were normal or had returned to normal. Furthermore, statistically significant differences were observed in absolute lymphocyte count, ferritin, and fibrinogen levels among the other four groups (P &lt; 0.05). Conclusions: Electrocardiogram findings in patients measured serially appear to improve over time. Since patients with MIS-C may experience ECG abnormalities that could lead to arrhythmias, close monitoring and the establishment of standardized approaches are essential. Long-term ECG abnormalities were associated with a decrease in absolute lymphocyte count and elevated levels of troponin, ferritin, and fibrinogen.

Results from a Joined Prospective Study to Evaluate the Sensitivity of the In Vivo Dog QT Assay in Line with the ICH E14/S7B Q&A Best Practices.

The ICH E14/S7B Q&As highlighted the need for best practices concerning the design, execution, analysis, interpretation, and reporting of the in vivo non-rodent QT assay as a component of the integrated risk assessment to potentially support a TQT waiver or substitute. We conducted a dog telemetry study to assess the effects on QTc of six reference compounds (five positive and one negative) previously evaluated by Darpo et al. (2015) in humans. The sensitivity of the assay to detect QTc increases was determined, and exposure-response analysis was performed, as done in clinical practice. By-timepoint analysis showed QTc prolongation induced by moxifloxacin, dofetilide, dolasetron, ondansetron, and quinine within human relevant plasma exposures ranges. Moreover, a hysteresis was observed for quinine. As expected, levocetirizine showed no statistically significant effect on QTc across a range of exposure, well exceeding the therapeutic Cmax. Power analyses confirmed the study ability to detect statistically significant QTc changes of less than 10 milliseconds with 80% probability, even with a sample size as low as n = 4 animals. Finally, concentration-QTc modeling enabled to predict the minimal plasma concentration needed to detect a 10 milliseconds QTc prolongation, including for quinine. The comparison with clinical available data supported the relevance of dogs under these experimental conditions as a robust translational predictor of drug-induced QTc prolongation in humans as a key pillar of the integrated risk assessment.

0553 Changes in QTc and QT Variability in Patients with OSA with and Without Heart Failure with PAP Based on Sleep Stage

0553 Changes in QTc and QT Variability in Patients with OSA with and Without Heart Failure with PAP Based on Sleep Stage

Association Between Disturbed Serum Phosphorus Levels and QT Interval Prolongation

Association Between Disturbed Serum Phosphorus Levels and QT Interval Prolongation

Beat-to-beat cardiac repolarization lability increases during hypoxemia and arousals in obstructive sleep apnea patients.

Obstructive sleep apnea (OSA) is associated with the progression of cardiovascular diseases, arrhythmias, and sudden cardiac death (SCD). However, the acute impacts of OSA and its consequences on heart function are not yet fully elucidated. We hypothesized that desaturation events acutely destabilize ventricular repolarization, and the presence of accompanying arousals magnifies this destabilization. Ventricular repolarization lability measures, comprising heart rate corrected QT (QTc), short-time-variability of QT (STVQT), and QT variability index (QTVI), were calculated before, during, and after 20,955 desaturations from lead II electrocardiography signals of 492 patients with suspected OSA (52% men). Variations in repolarization parameters were assessed during and after desaturations, both with and without accompanying arousals, and groupwise comparisons were performed based on desaturation duration and depth. Regression analyses were used to investigate the influence of confounding factors, comorbidities, and medications. The standard deviation (SD) of QT, mean QTc, SDQTc, and STVQT increased significantly (P < 0.01), whereas QTVI decreased (P < 0.01) during and after desaturations. The changes in SDQT, mean QTc, SDQTc, and QTVI were significantly amplified (P < 0.01) in the presence of accompanying arousals. Desaturation depth was an independent predictor of increased SDQTc (β = 0.405, P < 0.01), STVQT (β = 0.151, P < 0.01), and QTVI (β = 0.009, P < 0.01) during desaturation. Desaturations cause acute changes in ventricular repolarization, with deeper desaturations and accompanying arousals independently contributing to increased ventricular repolarization lability. This may partially explain the increased risk of arrhythmias and SCD in patients with OSA, especially when the OSA phenotype includes high hypoxic load and fragmented sleep.NEW & NOTEWORTHY Nocturnal desaturations are associated with increased ventricular repolarization lability. Deeper desaturations with accompanying arousals increase the magnitude of alterations, independent of confounding factors, comorbidities, and medications. Changes associated with desaturations can partially explain the increased risk of arrhythmias and sudden cardiac death in patients with OSA, especially in patients with high hypoxic load and fragmented sleep. This highlights the importance of detailed electrocardiogram analytics for patients with OSA.

QTc Shortening on Electrocardiogram With Amitriptyline May Indicate No Effect on Pain Relief in Burning Mouth Syndrome.

Burning mouth syndrome (BMS) is an intractable chronic pain disorder characterized by a burning sensation without organic abnormalities in the oral mucosa. Amitriptyline may be effective for BMS or, conversely, may exacerbate pain. QTc is necessary for monitoring psychotropic adverse effects, but it is not known if it is a predictor of efficacy for BMS. We investigated the efficacy of amitriptyline in BMS and its effect on QTc. Visual analog scale and electrocardiogram were examined before and 1 month after treatment in 51 consecutive patients diagnosed with BMS according to the International Classification of Headache Disorders, Third Edition (ICHD-3), criteria and treated with amitriptyline. There were 26 amitriptyline responders and 25 nonresponders, with no differences in age, sex, and amitriptyline dosage. Amitriptyline responders showed little change in QTc, whereas nonresponders showed a trend toward significantly shorter QTc. Changes in visual analog scale correlated statistically significantly with changes in QTc (Spearman rank correlation coefficient: 0384; P = 0.0054). The degree of pain tended to worsen with QTc shortening. Amitriptyline provides analgesia in about half of BMS patients, but some BMS patients have worse pain with amitriptyline. Not only do changes in the QTc detect amitriptyline adverse effects with prolongation, but also, conversely, its shortening predicts amitriptyline ineffectiveness.