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Multidrug resistant tuberculosis and non-tuberculous mycobacterium infections present challenges due to complex treatment regimens. Extended treatment regimes expose patients to higher risks of toxic side-effects. A high drug toxicity profile necessitates closer monitoring. One of the more challenging issues is QTc prolongation with non-injectable regimens.This study investigates the portable AliveCor device to record and measure the QTc on a 6-lead ECG. An automated QTc readout from 12-Lead ECG for each patient (n = 13) and mean QTc value calculated from each patients’ respective AliveCor tracing were compared. The general trend suggests AliveCor underestimates QTc − 92% cases calculated the AliveCor QTc as lower than their corresponding 12-Lead QTc readout.The use of AliveCor could potentially be translated into current clinical practice with caution of percentage variation either side. This could facilitate the use of AliveCor as a promising and convenient screening tool before further evaluation by a 12-Lead ECG is required.

Background: Persistence of Ebola virus (EBOV) in semen remains of deep concern, as sexual transmission of EBOV seems plausible up to 6 months after acute phase of Ebola virus disease (EVD). Favipiravir, a broad spectrum antiviral product, has been evaluated in reducing EVD mortality in Guinea in 2014–2015 in the JIKI trial, the pharmacokinetic results of which suggest that an increase of dose might be necessary to achieve a therapeutically relevant exposure. In FORCE trial, we aimed at evaluating the tolerance and activity of high doses of favipiravir in male EVD survivors with EBOV RNA detection in semen in Guinea. Case: In 2016, we launched a phase IIa open-labeled multicenter dose escalation study. Male survivors of EVD with EBOV RT-PCR positive on semen received a loading dose of 2400 mg BID of favipiravir on day 1 then a maintenance dose of 1800 mg BID from day 2–14. The primary outcome was the tolerance, assessed daily during period treatment and up to day 90. Unfortunately only two participants were included and the trial was stopped for lack of recruitment. No clinical adverse event of grade 3/4 was reported for both patients. One patient experienced a grade 3 hypocalcemia at day 10 and 14. Conclusions: High doses of favipiravir were well tolerated in these two participants. Better characterized tolerance and pharmacokinetics of high doses of favipiravir are of utmost importance considering that favipiravir is a candidate treatment for a variety of emerging severe viral diseases with poor prognosis.

Objectives: Pregnancy-related physiological adaptations result in increased heart rate as well as electrocardiographic changes such as a mean QTc prolongation of 27 ms. Pregnant women with CHD are at increased risk for cardiovascular complications. The aim of this study was to identify risk factors for abnormally prolonged QTc interval-a risk factor for ventricular arrhythmias-in pregnant women with CHD., Material and Method: Retrospective longitudinal single-centre study. Pre-pregnancy demographic and electrocardiographic risk factors for abnormal QTc duration during pregnancy of (a) > 460 ms and (b) >27 ms increase were analyzed., Results: Eighty-three pregnancies in 63 women were included, of which three had documented arrhythmias. All five Modified World Health Organization Classification of Maternal Cardiovascular Risk (mWHO) classes were represented, with 15 pregnancies (18.1%) in mWHO class I, 26 (31.3%) in mWHO II, 28 (33.7%) in mWHO II-III, 11 (13.3%) in mWHO III, and three pregnancies (3.6%) in mWHO class IV. Heart rate and QTc interval increased, while QRS duration and PR interval shortened during pregnancy. QTc duration of > 460 ms was associated with increased pre-pregnancy QTc interval, QRS duration, and weight, as well as body mass index. QTc increase of > 27 ms was associated with increased heart rate prior to pregnancy. No significant associations of electrocardiographic changes with mWHO class or CHD type were identified., Conclusion: Increased QTc in pregnant women with CHD was associated with being overweight or having higher heart rate, QRS, or QTc duration prior to pregnancy. These patients should be monitored closely for arrhythmias during pregnancy.

Background Human glucagon-like peptide-1 analogue, Liraglutide, has shown cardioprotective effects in animal and clinical studies of type 2 diabetes mellitus. This study was conducted to assess the effect of Liraglutide on diabetes-induced myocardial electrical remodeling. Materials and Methods A rat model of type 2 diabetes mellitus was induced by high-fat diet and low dose Streptozotocin (35 mg/kg). Diabetic rats were randomized into 4 subgroups (n=6–7): diabetic-untreated, diabetics treated with Liraglutide, diabetics treated with Ramipril, and diabetics treated with Metformin in addition to a control group. Changes in serum glucose, insulin, lipid profile and revised quantitative insulin sensitivity check index (QUICKI index) were assessed. QT and QTc intervals were measured and the degree of cardiac interstitial and perivascular fibrosis was examined. The expression of myocardial Ito channel α subunits, gap junction protein; Kv 4.2/4.3 and connexin 43 (Cx43) respectively, were assessed by western blotting and immunohistochemistry. Results Similar to Ramipril, both Liraglutide and Metformin effectively inhibited the diabetes-induced myocardial hypertrophy and fibrosis. However, Liraglutide treatment significantly improved Kv 4.2/4.3 and Cx43 expression/distribution and prevented diabetes-related QTc interval prolongation. Conclusions We have shown that pathological alterations in myocardial Cx43 expression and distribution, in addition to reduced Ito channel expression, may underlie the QTc interval prolongation in high-fat diet/STZ rat model of type 2 diabetes mellitus. The beneficial effects of Liraglutide, as those of Ramipril, on cardiac electrophysiology could be at least attributed to its direct ability to normalize expression and distribution of Cx43 and Ito channels in the diabetic rat heart. [ABSTRACT FROM AUTHOR]

Objective: COVID-19; It spread rapidly around the world and led to a global pandemic. Indicators of poor prognosis are important in the treatment and follow-up of COVID-19 patients and have always been a matter of interest to researchers. The aim of this study was to investigate the relationship between frontal QRS-T angle values and clinical severity and prognosis in COVID-19 patients.Methods: This prospective case-control study was conducted with 130 COVID-19 patients whose diagnosis was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) and 100 healthy controls. The CURB-65 score was used as the clinical severity score.Results: A total of 130 patients and 100 healthy controls were included in the study. When the patient and control groups were compared a significant difference was found between QT (378.07 ± 33.75 vs. 368.63 ± 19.65, p < 0.001), QTc (410.79 ± 28.19 vs. 403.68 ± 11.70, p < 0.001), QRS time (95.04 ± 21.67 vs. 91.42 ± 11.08, p < 0.001) and frontal QRS-T angle (36.57 ± 22.86 vs. 22.72 ± 14.08, p < 0.001). According to clinical severity scoring, QT (370.27 ± 25.20 vs. 387.75 ± 40.19, p = 0.003), QTc (402.18 ± 19.92 vs. 421.48 ± 33.08, p < 0.001), frontal QRS-T angle (32.25 ± 18.79 vs. 41.94 ± 26.27), p = 0.0.16) parameters were found to be significantly different. Age (odds ratio [OR], 1.201; 95% confidence interval [CI], 1.111-1.298; p < 0.001) and frontal QRS-T angle ([OR], 1.045; 95% [CI], 1.015-1.075; p = 0.003) values were found to be an independent predictor for the severity of the disease. Frontal QRS-T angle ([OR], 1.101; 95% [CI], 1.030-1.176; p = 0.004), and CRP ([OR], 1.029; 95% [CI], 1.007-1.051; p = 0.01) parameters were found to be independent predictors for the mortality of the disease. As a mortality indicator; for the frontal QRS-T angle of ≥44.5°, specificity and sensitivity were 93.8% and 84.2%, respectively.Conclusion: Frontal QRS-T angle can be used as a reproducible, convenient, inexpensive, new and powerful predictor in determining the clinical severity and prognosis of COVID-19 patients. [ABSTRACT FROM AUTHOR]

Background: Hypoglycemia is the most common complication in insulin treated diabetes. Though mostly mild, it can be fatal in rare cases: It is hypothesized that hypoglycemia related QTc prolongation contributes to cardiac arrhythmia. Objective: To evaluate influence of nocturnal hypoglycemia on QTc and heart rate variability (HRV) in children with T1D. Methods: Children and adolescents with T1D for at least 6 months participated in an observational study using continuous glucose monitoring (CGM) and Holter electrocardiogram for five consecutive nights. Mean QTc was calculated for episodes of nocturnal hypoglycemia (<3.7 mmol/L) and compared to periods of the same duration preceding hypoglycemia. HRV (RMSSD, low and high frequency power LF and HF) was analyzed for different 15 min intervals: before hypoglycemia, onset of hypoglycemia, before/after nadir, end of hypoglycemia and after hypoglycemia. Results: Mean QTc during hypoglycemia was significantly longer compared to euglycemia (412 ± 15 vs. 405 ± 18 ms, p = 0.005). HRV changed significantly: RMSSD (from 88 ± 57 to 73 ± 43 ms) and HF (from 54 ± 17 to 47 ± 17nu) decreased from before hypoglycemia to after nadir, while heart rate (from 69 ± 9 to 72 ± 12 bpm) and LF (from 44 ± 17 to 52 ± 21 nu) increased (p = 0.04). Conclusion: A QTc lengthening effect of nocturnal hypoglycemia in children with T1D was documented. HRV changes occurred even before detection of nocturnal hypoglycemia by CGM, which may be useful for hypoglycemia prediction. [ABSTRACT FROM AUTHOR]

Background: β‐Blockers are first‐line therapy in patients with long QT syndrome (LQTS). However, β‐blockers had genotype dependent efficacy (LQT1>LQT2>LQT3). Sodium channel blockers have been recommended as add‐on therapy for LQT3 patients. However, the pooled effect of sodium channel blockers in all LQTS patients remains unknown. Methods: We conducted a systematic electronic search of PubMed, Embase, and the Cochrane Library. Fixed effects model was used to assess the effect of sodium channel blockers on QTc, cardiac events (CEs), and the proportion of QTc ≥ 500 ms and QTc ≤ 460 ms in LQTS patients. Results: Pooled analysis of 14 studies with 213 LQTS (9 LQT1 + 63 LQT2 + 135 LQT3 + 6 others) patients showed that sodium channel blockers significantly shortened QTc by nearly 50 ms (mean difference [MD], −49.43; 95% confidence interval [CI], −57.80 to −41.05, p <.001), reduced the incidence of CEs (risk ratio [RR], 0.23; 95% CI, 0.11–0.47; p <.001) and the proportion of QTc ≥ 500 ms (RR, 0.33; 95% CI, 0.24–0.47; p <.001), and increased the proportion of QTc ≤ 460 ms (RR, 10.33; 95% CI, 4.62–23.09; p <.001). Sodium channel blockers significantly shortened QTc both in LQT3 and LQT2 patients, while the QTc shortening effect in LQT3 was superior to that in LQT2 (57.39 vs. 36.61 ms). Mexiletine, flecainide, and ranolazine all significantly shortened QTc, and the QTc shortening effect by mexiletine was the best (60.70 vs. 49.08 vs. 50.10 ms). Conclusions: Sodium channel blockers can be useful both in LQT3 and LQT2 patients. Mexiletine, flecainide and ranolazine significantly shortened QTc in LQTS patients, and the QTc shortening effect by mexiletine was the best. [ABSTRACT FROM AUTHOR]

Background: Interval duration measurements (IDMs) were compared between standard 12-lead electrocardiograms (ECGs) and 6-lead ECGs recorded with AliveCor's KardiaMobile 6L, a hand-held mobile device designed for use by patients at home. Methods: Electrocardiograms were recorded within, on average, 15 min from 705 patients in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic. Interpretable 12-lead and 6-lead recordings were available for 685 out of 705 (97%) eligible patients. The most common diagnosis was congenital long QT syndrome (LQTS, 343/685 [50%]), followed by unaffected relatives and patients (146/685 [21%]), and patients with other genetic heart diseases, including hypertrophic cardiomyopathy (36 [5.2%]), arrhythmogenic cardiomyopathy (23 [3.4%]), and idiopathic ventricular fibrillation (14 [2.0%]). IDMs were performed by a central ECG laboratory using lead II with a semi-automated technique. Results: Despite differences in patient position (supine for 12-lead ECGs and sitting for 6-lead ECGs), mean IDMs were comparable, with mean values for the 12-lead and 6-lead ECGs for QTcF, heart rate, PR, and QRS differing by 2.6 ms, -5.5 beats per minute, 1.0 and 1.2 ms, respectively. Despite a modest difference in heart rate, intervals were close enough to allow a detection of clinically meaningful abnormalities. Conclusions: The 6-lead hand-held device is potentially useful for a clinical follow-up of remote patients, and for a safety follow-up of patients participating in clinical trials who cannot visit the investigational site. This technology may extend the use of 12-lead ECG recordings during the current COVID-19 pandemic as remote patient monitoring becomes more common in virtual or hybrid-design clinical studies. [ABSTRACT FROM AUTHOR]

In August 2020, the International Council on Harmonisation (ICH) released a new draft document, which for the first time combined nonclinical (S7B) and clinical (E14) Questions and Answers (Q&As) into 1 document. FDA describes the revision as a "value proposition": if the human ether‐à‐go‐go assay and the in vivo study are performed in a standardized way, the number of dedicated thorough QT (TQT) studies can be reduced. In this article, we describe and discuss the Q&As that relate to clinical ECG evaluation. If supported by negative standardized nonclinical assays, Q&A 5.1 will obviate the need for a TQT study in the case that a >2‐fold exposure margin vs high clinical scenario cannot be obtained. Q&A 6.1 addresses drugs that are poorly tolerated in healthy subjects and cannot be studied at high doses or in placebo‐controlled studies; it therefore mainly applies to oncology drugs. It will enable sponsors to claim that a new drug has a "low likelihood of proarrhythmic effects" in the case that the mean corrected QT effect is <10 milliseconds at the time of market application. The E14 2015 revision allowed application of concentration–corrected QT analysis on data from routinely performed clinical pharmacology studies, for example, the first‐in‐human study and the proportion of dedicated TQT studies has since steadily decreased. It can be foreseen that the proposed new revision will further reduce the number of TQT studies. To achieve harmonization across regulatory regions, it seems important to reach consensus within the International Council on Harmonisation group on the new threshold proposed in 6.1. For this purpose, the Implementation Working Group has asked for public comments. [ABSTRACT FROM AUTHOR]

Studies on the effects of memantine on QT prolongation have yielded conflicting results. For a long time, memantine was reported to be a safe drug without QT prolongation; however, several case studies have reported memantine‐induced QT prolongation in Alzheimer's patients. This study evaluated the relationship between memantine blood levels, and QT interval changes. Over a 2‐week period, we orally administered 20 mg of memantine daily to achieve a steady state in 57 healthy Korean subjects. We measured and analyzed the QT interval and blood memantine concentrations simultaneously before and after treatment, as well as 2 weeks after the last dosing. Correlation analysis was done between blood memantine level and QT interval. No serious adverse events occurred during the study period. Repeated dosing of memantine did not show clinically significant QT interval changes after treatment. Regression analysis was performed based on the results; there was no statistical association between memantine blood level and QT prolongation. In conclusion, the results of the present study demonstrated no clinically significant changes in the QT interval with therapeutic blood levels of memantine. [ABSTRACT FROM AUTHOR]

Background: Self-medication and acquisition of over-the-counter (QTC) drugs are emerging community health issues. Besides being a cheap alternative for treating common illnesses, the behavior entails serious ramifications, such as medication wastage, increasing pathogen resistance, and adverse drug reactions. So, the purpose of the present study was to explore and understand the consumption of commonly used QTC drugs and dietary supplements in Dubai and also assess individuals' self-care behaviors related to QTC and dietary supplements. Methodology: A cross-sectional study design was adopted in the present study and 200 participants were included in this study. Data was entered and analyzed through SPSS version 22. While the chi-square test was conducted to find out significance among variables. Findings: Results from the current study showed that more than a quarter of the participants (31%) were male and 69% of them were females. The prevalence of QTC drugs and dietary supplements was higher (98%) among the individuals living in Dubai. The majority of participants (80%) used analgesics as QTC drugs. Results also revealed that 35.5% of participants used vitamins on a daily basis, 11% used them on weekly basis, and 5.5% used them on monthly basis. While 79.5% of participants obtained their QTC drugs and dietary supplements from community pharmacies. Conclusion: This study provides significant findings regarding an individual's knowledge and behavior for utilizing QTC drugs and dietary supplements. The result has drawn from the present study can help the policymakers, and stakeholders to promulgate and effectiveness of policies and program implementation within the country. Lastly future studies with larger samples are required for the generalizability of the study results. [ABSTRACT FROM AUTHOR]

Abstract Background Interval duration measurements (IDMs) were compared between standard 12‐lead electrocardiograms (ECGs) and 6‐lead ECGs recorded with AliveCor's KardiaMobile 6L, a hand‐held mobile device designed for use by patients at home. Methods Electrocardiograms were recorded within, on average, 15 min from 705 patients in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic. Interpretable 12‐lead and 6‐lead recordings were available for 685 out of 705 (97%) eligible patients. The most common diagnosis was congenital long QT syndrome (LQTS, 343/685 [50%]), followed by unaffected relatives and patients (146/685 [21%]), and patients with other genetic heart diseases, including hypertrophic cardiomyopathy (36 [5.2%]), arrhythmogenic cardiomyopathy (23 [3.4%]), and idiopathic ventricular fibrillation (14 [2.0%]). IDMs were performed by a central ECG laboratory using lead II with a semi‐automated technique. Results Despite differences in patient position (supine for 12‐lead ECGs and sitting for 6‐lead ECGs), mean IDMs were comparable, with mean values for the 12‐lead and 6‐lead ECGs for QTcF, heart rate, PR, and QRS differing by 2.6 ms, −5.5 beats per minute, 1.0 and 1.2 ms, respectively. Despite a modest difference in heart rate, intervals were close enough to allow a detection of clinically meaningful abnormalities. Conclusions The 6‐lead hand‐held device is potentially useful for a clinical follow‐up of remote patients, and for a safety follow‐up of patients participating in clinical trials who cannot visit the investigational site. This technology may extend the use of 12‐lead ECG recordings during the current COVID‐19 pandemic as remote patient monitoring becomes more common in virtual or hybrid‐design clinical studies.

Background: Infarction of the medulla has been associated with prolongation of the QTc, severe arrhythmia, and sudden cardiac death, yet the precise anatomical substrate remains uncertain. Aims: We sought to determine the possible anatomical structures relating to QTc‐prolongation in patients with acute medullary infarction. Methods: We included 12 subjects with acute ischemic medullary infarction on brain MRI, who presented within 4.5 h from the last known well time, with a 90‐day follow‐up. For an unbiased lesion analysis, medullary infarcts were manually outlined on diffusion weighted MRI and co‐registered with an anatomical atlas. Results: Nine out of 12 had QTc‐prolongation. Qualitative and semi‐quantitative comparisons were made between infarct location and QTc‐prolongation. Among patients with QTc‐prolongation, the greatest degree of congruence of the infarct location was over the dorsal vagal nucleus (DVN, 8 out of 9). There was a significant correlation between the number of sections showing infarction of the DVN and presence of QTc‐prolongation (r =.582, p =.047). Among patients without QTc‐prolongation, the maximum lesion overlap included the medial aspect of the gigantocelluar reticular nucleus of the reticular formation. Conclusion: We found that the DVN is a key anatomical substrate related to QTc‐prolongation. Further studies with more patients and high‐resolution, volumetric MRI are needed to confirm our findings. [ABSTRACT FROM AUTHOR]

Background/Aim: Coronavirus Disease 2019 (Covid-19) is a pandemic with fatal effects on the respiratory and cardiovascular systems. Early recognition of complications in the cardiovascular system in Covid-19 disease will guide our treatment management. Therefore, we aimed to examine the changes that occurred in the ECGs of patients with a Covid-19 infection in the last year who were admitted with palpitations. Methods: Patients who presented to the Cardiology and Internal Medicine outpatient clinics with a complaint of palpitation between June 2021 and July 2021 and who had a Covid-19 infection in the last year were included in this study. A total of 212 patients with a history of Covid-19 and a control group of 185 people without Covid-19 history and cardiac diseases were compared. At admission, QTc, Tp-e interval, frontal QRS-T angle, and fragmented QRS were evaluated on Electrocardiography (ECG). Results: Among patients with a history of Covid-19 disease, there were 127 (59.91%) males and 85 (40.09%) females. Within the control group, 71 (38.38%) were males and 114 (61.62%) were females. In patients who had a Covid-19 infection, QTc (OR: 1.071, 95% CI: 1.042-1.100, P<0.001), frontal QRS-T angle (OR: 1.054, 95% CI: 1.015-1.095, P=0.007), and Tp-e interval (OR: 1.253, 95% CI: 1.140-1.377, P<0.001) were significantly increased. The difference in fragmented QRS (P=0.230) was not significant in logistic regression analysis. Conclusion: We found increased QTc, Tp-e, and fQRS-T angles in patients who had Covid-19 disease, all of which indicate ventricular repolarization abnormality. Therefore, those with Covid-19 infection should be followed up for malignant arrhythmias. [ABSTRACT FROM AUTHOR]

Arrhythmia, one of the most common complications of COVID-19, was reported in nearly one-third of diagnosed COVID-19 patients, with higher prevalence rate among ICU admitted patients. The underlying etiology for arrhythmia in these cases are mostly multifactorial as those patients may suffer from one or more of the following predisposing mechanisms; catecholamine surge, hypoxia, myocarditis, cytokine storm, QTc prolongation, electrolyte disturbance, and pro-arrhythmic drugs usage. Obviously, the risk for arrhythmia and the associated lethal outcome would rise dramatically among patients with preexisting cardiac disease such as myocardial ischemia, heart failure, cardiomyopathy, and hereditary arrhythmias. Considering all of these variables, the management strategy of COVID-19 patients should expand from managing a viral infection and related host immune response to include the prevention of predictable causes for arrhythmia. This may necessitate the need to investigate the role of some drugs that modulate the pathway of arrhythmia generation. Of these drugs, we discuss the potential role of adrenergic antagonists, trimetazidine, ranolazine, and the debatable angiotensin converting enzyme inhibitors drugs. We also recommend monitoring the level of: unbound free fatty acids, serum electrolytes, troponin, and QTc (even in the absence of apparent pro-arrhythmic drug use) as these may be the only indicators for patients at risk for arrhythmic complications. [ABSTRACT FROM AUTHOR]

Background: Metabolic syndrome comprises a group of disorders, including cardiac abnormalities. Ventricular arrhythmias observed in metabolic syndrome are due to the impaired ventricular repolarization. This study aims to determine the effects of melatonin on cardiac ventricular repolarization in metabolic syndrome rat model. Methods and results: Sprague–Dawley rats were divided into control (n = 8), melatonin (n = 8), metabolic syndrome (n = 8) and metabolic syndrome + melatonin (n = 8) groups. Fructose (200 g/lt/day) was added into the drinking water during 8 weeks of rats to induce metabolic syndrome model. In the last two weeks, melatonin (20 mg/kg/day) was administered via oral gavage. Blood pressure measurements and ECG recordings were taken at three different times. Blood and left ventricular tissue samples were harvested and the KCNQ1,3 and KCNH2 gene expressions were analysed by qRT-PCR method. We observed insulin resistance, hyperglycemia, dyslipidemia and higher systolic blood pressure in metabolic syndrome group (p < 0.01, for all). Prolonged QT interval was observed in metabolic syndrome group (p < 0.001). The expression levels of the KCNQ genes encoding the Kv7 channel was significantly reduced, however KCNH2 gene which encodes Kv11.1 channel was increased in metabolic syndrome group compared to control group (p < 0.05, p < 0.001, respectively). Melatonin significantly normalised the prolongation on QT interval in metabolic syndrome group (p < 0.001) and the expressions of the KCNQ (p < 0.002) and KCNH2 genes (p = 0.003). Conclusions: The present study revealed that melatonin had ameliorative effects on ventricular repolarization by improving the prolonged QT duration in rats with metabolic syndrome and this effect was generated by the KCNQ and KCNH2 gene families. [ABSTRACT FROM AUTHOR]

Background: Minimizing direct patient contact among healthcare personnel is crucial for mitigating infectious risk during the coronavirus disease 2019 (COVID-19) pandemic. The use of remote cardiac telemetry as an alternative to 12‑lead electrocardiography (ECG) for continuous QTc monitoring may facilitate this strategy, but its application has not yet been validated or implemented.Methods: In the validation component of this two-part prospective cohort study, a total of 65 hospitalized patients with simultaneous ECG and telemetry were identified. QTc obtained via remote telemetry as measured by 3 independent, blinded operators were compared with ECG as assessed by 2 board-certified electrophysiologists as the gold-standard. Pearson correlation coefficients were calculated to measure the strength of linear correlation between the two methods. In a separate cohort comprised of 68 COVID-19 patients treated with combined hydroxychloroquine and azithromycin, telemetry-based QTc values were compared at serial time points after medication administration using Friedman rank-sum test of repeated measures.Results: Telemetry-based QTc measurements highly correlated with QTc values derived from ECG, with correlation coefficients of 0.74, 0.79, 0.85 (individual operators), and 0.84 (mean of all operators). Among the COVID-19 cohort, treatment led to a median QTc increase of 15 milliseconds between baseline and following the 9th dose (p = 0.002), with 8 (12%) patients exhibiting an increase in QTc ≥ 60 milliseconds and 4 (6%) developing QTc ≥ 500 milliseconds.Conclusions: Cardiac telemetry is a validated clinical tool for QTc monitoring that may serve an expanding role during the COVID-19 pandemic strengthened by its remote and continuous monitoring capability and ubiquitous presence throughout hospitals. [ABSTRACT FROM AUTHOR]

Cardiovascular safety pharmacology and toxicology studies include vehicle control animals in most studies. Electrocardiogram data on common vehicles is accumulated relatively quickly. In the interests of the 3Rs principles it may be useful to use this historical information to reduce the use of animals or to refine the sensitivity of studies. We used implanted telemetry data from a large nonhuman primate (NHP) cardiovascular study (n = 48) evaluating the effect of moxifloxacin. We extracted 24 animals to conduct a n = 3/sex/group analysis. The remaining 24 animals were used to generate 1000 unique combinations of 3 male and 3 female NHP to act as control groups for the three treated groups in the n = 3/sex/group analysis. The distribution of treatment effects, median minimum detectable difference (MDD) values were gathered from the 1000 studies. These represent contemporary controls. Data were available from 42 NHP from 3 other studies in the same laboratory using the same technology. These were used to generate 1000 unique combinations of 6, 12, 18, 24 and 36 NHP to act as historical control animals for the 18 animals in the treated groups of the moxifloxacin study. Data from an additional laboratory were also available for 20 NHP. The QT, RR and QT-RR data from the three sources were comparable. However, differences in the time course of QTc effect in the vehicle data from the two laboratories meant that it was not possible to use cross-lab controls. In the case of historical controls from the same laboratory, these could be used in place of the contemporary controls in determining a treatment's effect. There appeared to be an advantage in using larger (≥18) group sizes for historical controls. These data support the opportunity of using historical controls to reduce the number of animals used in new cardiovascular studies. [ABSTRACT FROM AUTHOR]

Gepirone was recently launched and FDA-approved for MDD. It belongs to azapirones group of psychotropics that is in popular use in Japan and China. Here, author wraps up current knowledge on gepirone contrasted with the older and cheaper anxiolytic buspirone. [ABSTRACT FROM AUTHOR]

Aim: To assess the efficacy and safety of hydroxychloroquine with or without azithromycin) in hospitalized adult patients with COVID-19. Methods: We utilized a hospital based prospective data registry. The primary end point was to assess the impact of hydroxychloroquine with or without azithromycin, on outcome, length of hospitalization, and time to clinical improvement. We utilized treatment effects with inverse-probability-weighting and Cox proportional hazards models. All analyses accounted for age, gender, race, severity on admission, days from symptoms onset and chronic comorbidities. Results: 36 patients received hydroxychloroquine and were age- and sex-matched to 72 patients with COVID-19 who received supportive care. Compared to supportive care, the use of HCQ did not shorten the time to clinical improvement (+0.23 days; 95% CI: −1.8–2.3 days) nor did it shorten the duration of hospital stay (+0.91 days; 95% CI: −1.1–2.9 days). Additionally, HCQ did not decrease the risk of COVID-19 in-hospital death (aHR 1.67; 95% CI: 0.29–9.36). Finally, we observed a slight QTc prolongation from a baseline of 444 ± 26 ms to 464 ± 32 ms (mean±SD) among patients receiving hydroxychloroquine with or without azithromycin. Conclusion: This study did not yield benefits from hydroxychloroquine use in patients with COVID-19 and monitoring for adverse events is warranted. Nevertheless, the treatment was safely studied under the guidance of an antimicrobial stewardship program.

We assessed torsadogenic action of risperidone, which can potently inhibit IKr as well as α1-adrenoceptor. A toxic dose of 3 mg/kg of risperidone was intravenously administered over 10 min to chronic atrioventricular block dogs without anesthesia with monitoring Holter electrocardiogram (n = 4). Risperidone increased atrial/ventricular rate for 1–12 h/1–6 h and prolonged QTcF at 6 h after its administration, whereas it did not increase short-term variability of repolarization or induced torsade de pointes. These results suggest that α1-adrenoceptor blockade-dependent, hypotension-induced, reflex-mediated increase of sympathetic tone by risperidone might play a role in protecting the heart from IKr inhibition-associated torsade de pointes.

Abstract Background The direction of the current research was to investigate whether electrocardiogram (ECG) signals have been impacted by using compression garments during exercise and recovery phase. Each subject is non-athletes, conducted two running tests, wearing either non-compression garments (NCGs) or compression garments (CGs) throughout experiments and 2-h of the recovery phase. Experiment 1 (number of participants (n) = 8; 61.4 ± 13.7 kg, 25.1 ± 3.8 years, 165.9 ± 8.3 cm) focused on the exercising phase while Experiment 2 (n = 14; 60.9 ± 12.0 kg, 24.7 ± 4.5 years, 166.0 ± 7.6 cm) concentrated on the recovery phase. Electrocardiogram (ECG) data were collected through wearable biosensors. Results The results demonstrated a significant difference between compression garments and non-compression garments at the end of the tests and from 90 min onwards during the recovery phase (p

Changes in the cardio-metabolomics profile and hormonal status have been associated with long QT syndrome, sudden cardiac death and increased mortality. The mechanisms underlying QTc duration are not fully understood. Therefore, an identification of novel markers that complement the diagnosis in these patients is needed. In the present study, we performed untargeted metabolomics on the sera of diabetic patients at a high risk of cardiovascular disease, followed up for 2.55 [2.34–2.88] years (NCT02431234), with the aim of identifying the metabolomic changes associated with QTc. We used independent weighted gene correlation network analysis (WGCNA) to explore the association between metabolites clusters and QTc at T1 (baseline) and T2 (follow up). The overlap of the highly correlated modules at T1 and T2 identified N-Acetyl asparagine as the only metabolite in common, which was involved with the urea cycle and metabolism of arginine, proline, glutamate, aspartate and asparagine. This analysis was confirmed by applying mixed models, further highlighting its association with QTc. In the current study, we were able to identify a metabolite associated with QTc in diabetic patients at two chronological time points, suggesting a previously unrecognized potential role of N-Acetyl asparagine in diabetic patients suffering from long QTc.

Background: QTc prolongation is an adverse effect of COVID-19 therapies. The use of a handheld device in this scenario has not been addressed. Objectives: To evaluate the feasibility of QTc monitoring with a smart device in COVID-19 patients receiving QTc-interfering therapies. Methods: Prospective study of consecutive COVID-19 patients treated with hydroxychloroquine ± azithromycin ± lopinavir-ritonavir. ECG monitoring was performed with 12-lead ECG or with KardiaMobile-6L. Both registries were also sequentially obtained in a cohort of healthy patients. We evaluated differences in QTc in COVID-19 patients between three different monitoring strategies: 12-lead ECG at baseline and follow-up (A), 12-lead ECG at baseline and follow-up with the smart device (B), and fully monitored with handheld 6-lead ECG (group C). Time needed to obtain an ECG registry was also documented. Results: One hundred and eighty-two COVID-19 patients were included (A: 119(65.4%); B: 50(27.5%); C: 13(7.1%). QTc peak during hospitalization did significantly increase in all groups. No differences were observed between the three monitoring strategies in QTc prolongation (p = 0.864). In the control group, all but one ECG registry with the smart device allowed QTc measurement and mean QTc did not differ between both techniques (p = 0.612), displaying a moderate reliability (ICC 0.56 [0.19–0.76]). Time of ECG registry was significantly longer for the 12-lead ECG than for handheld device in both cohorts (p < 0.001). Conclusion: QTc monitoring with KardiaMobile-6L in COVID-19 patients was feasible. Time of ECG registration was significantly lower with the smart device, which may offer an important advantage for prevention of virus dissemination among healthcare providers.

The circadian rhythm of cardiac electrophysiology is dependent on many physiological and biochemical factors. Provided, that models describing the circadian patterns of cardiac activity and/or electrophysiology which have been verified to the acceptable level, modeling and simulation can give answers to many of heart chronotherapy questions. The aim of the study was to assess the performance of the circadian models implemented in Cardiac Safety Simulator v 2.2 (Certara, Sheffield, UK) (CSS), as well as investigate the influence ofcircadian rhythms on the simulation results in terms of cardiac safety. The simulations which were run in CSS accounted for inter-individual and intra-individual variability. Firstly, the diurnal variations in QT interval length in a healthy population were simulated accounting for heart rate (HR) circadian changes alone, or with concomitant diurnal variations of plasma ion concentrations. Next, tolterodine was chosen as an exemplary drug for PKPD modelling exercise to assess the role of circadian rhythmicity in the prediction of drug effects on QT interval. The results of the simulations were in line with clinical observations, what can serve as a verification of the circadian models implemented in CSS. Moreover, the results have suggested that the circadian variability of the electrolytes balance is the main factor influencing QT circadian pattern. The fluctuation of ion concentration increases the intra-subject variability of predicted drug-triggered QT corrected for HR (QTc) prolongation effect and, in case of modest drug effect on QTc interval length, allows to capture this effect. [ABSTRACT FROM AUTHOR]

Prolonged corrected QT (QTc) interval is a hallmark of cirrhotic cardiomyopathy (CCM) and has been ascertained to predict mortality in cirrhosis. However, some critical issues remain to be addressed including unanimous cut-off, calculation approach and applicable population. A total of 274 patients with cirrhosis were included. The prolonged QTc interval over 440 ms according to adjusted Fridericia's formula was used to stratify enrolled subjects. Independent predictors of 3-year mortality were identified with Cox regression model. The Kaplan–Meier method was implemented to obtain survival curves. To reduce impact of selection bias and possible confounders, a propensity score matching (PSM) analysis was used. QTc > 440 ms was an independent risk factor in the entire cohort and PSM subset (HR 2.532, 95% CI 1.431–4.480, p=.001; HR 2.802, 95% CI 1.171–6.701, p=.021, respectively). Subgroup analysis showed that QTc > 440 ms was an independent predictor in cirrhotics with age ≤60 years (HR = 1.02, p=.035) and in the presence of ascites (HR = 1.01, p=.008). The prolonged QTc interval might help to identify patients with high-risk of all-cause mortality. [ABSTRACT FROM AUTHOR]

Solriamfetol, a dopamine and norepinephrine reuptake inhibitor, is approved (United States and European Union; Sunosi) to treat excessive daytime sleepiness associated with narcolepsy (75‐150 mg/day) or obstructive sleep apnea (37.5‐150 mg/day). A thorough QT/QTc study assessed solriamfetol effects on QT interval (Fridericia correction for heart rate; QTcF). This randomized, double‐blind, placebo‐ and positive‐controlled, 4‐period crossover study compared single doses of 300 and 900 mg solriamfetol, 400 mg moxifloxacin, and placebo in healthy adults. Placebo‐ and predose‐adjusted mean differences in QTcF (ddQTcF; primary end point) were analyzed, and solriamfetol pharmacokinetics were characterized. Fifty‐five participants completed all periods. Upper bounds of 2‐sided 90% confidence intervals (CIs) for ddQTcF for both solriamfetol doses were <10 milliseconds at all postdose time points. Assay sensitivity was demonstrated with moxifloxacin; lower bounds of 2‐sided 90%CIs for ddQTcF > 5 milliseconds at 1, 2, and 3 hours postdose. There were no QTcF increases > 60 milliseconds or QTcF values > 480 milliseconds at either solriamfetol dose. Solriamfetol median tmax was 2‐3 hours; exposure was dose‐proportional. More participants experienced adverse events (AEs) after solriamfetol 900 versus 300 mg (70% vs 29%); none were serious (all mild/moderate), and there were no deaths. Common AEs were nausea, dizziness, and palpitations. Neither solriamfetol dose resulted in QTcF prolongation > 10 milliseconds. [ABSTRACT FROM AUTHOR]

The impact of repeated daily 500‐mg fedratinib (an oral selective Janus kinase [JAK] 2 inhibitor) on QTc and other electrocardiogram (ECG) parameters was assessed in 60 patients with advanced solid tumors. Patients received placebo on day 1 and fedratinib 500 mg daily for 14 days. Concentration‐QTc analysis was performed with change‐from‐baseline QTc corrected by Fridericia's formula (ΔQTcF) as the dependent variable. Fedratinib median time to maximum plasma concentration (Cmax) was observed 3 hours postdose on day 15. The largest difference between means for fedratinib and placebo was 0.5 bpm (90%CI, −2.75 to 3.72 bpm) for heart rate (3 hours postdose) and 4.3 milliseconds (90%CI, 1.04‐7.60 milliseconds) for QTcF (4 hours postdose). The estimated slope of the fedratinib concentration‐QTcF relationship was shallow and not statistically significant: −0.0005 milliseconds per ng/mL (90%CI, −0.00145 to 0.00050 milliseconds per ng/mL). Predicted fedratinib placebo‐corrected ΔQTcF was 0.6 milliseconds (90%CI, −1.80 to 2.93 milliseconds) at the geometric mean of the observed Cmax (3615 ng/mL). Fedratinib did not affect PR or QRS intervals. No patients had QTcF > 60 milliseconds, and no patients experienced QTcF ≥ 500 milliseconds. Fedratinib did not cause clinically relevant ECG effects or QTc prolongation. Safety findings were consistent with the known safety profile. [ABSTRACT FROM AUTHOR]

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

Background: ECG abnormalities associated with COVID‐19 pneumonia and adverse outcome are undefined and poorly described in prior studies. Objectives: To assess the predictive role of baseline ECG markers of increased risk of malignant arrhythmias and cardiac death for adverse in‐hospital outcomes. Patients and methods: A retrospective study included 93 patients of newly diagnosed COVID‐19 with features consistent with pneumonia who were admitted to the hospital from August 20 to September 20, 2020. The main outcomes were defined as receiving mechanical ventilation, in‐hospital cardiac arrest, length of ICU stay, and degree of lung damage according to computed tomography (CT) score. Results: Increased QTc (QT corrected) interval, Tp‐e (T from peak to end) interval, and transmural dispersion of repolarization (TDR) were independent predictors of prolonged ICU stay (P <.0001) after adjustment for baseline clinical characteristics. Increasing age (P <.0001) followed by increased QTc interval (P =.02) and history of chronic lung disease (P =.04) were independent predictors of extensive lung damage. The independent predictors for in‐hospital cardiac arrest were increased QTc (P =.02) followed by increasing age (P =.04) and increased Tp‐e interval (P =.04). Conclusion: Repolarization abnormalities on baseline ECG may be useful prognostic markers in patients with COVID‐19 pneumonia. [ABSTRACT FROM AUTHOR]

Early-phase studies quantifying the QTc prolongation potential for a new drug often use linear concentration-QTc (C-QTc) models, assuming no delay between plasma concentrations and QTc changes. However, that assumption is not always correct. The term "hysteresis" has been utilized to describe a time lag present between a measurable concentration and a measurable effect. To detect and quantify hysteresis and its impact on study interpretation, studies with hysteresis of 0.25–4 h were simulated with different doses, half-lives, and sampling schedules in a crossover design. Hysteresis was quantified using a novel method termed exposure-normalized GRI (enGRI), a proposed modification of the Glomb-Ring Index (GRI), to account for delay and magnitude of QTc effects. With realistic sampling, the rate of false negative studies (FN) increased proportionally to the delay, even for delays shorter than 1 h. Using an enGRI threshold (γ) of 2 ms resulted in FN with undetected delay and FN without hysteresis at approximately the same rate. For γ = 2 ms, the specificity of enGRI was > 90% throughout the investigated scenarios. We therefore propose the incorporation of enGRI when interpreting results from C-QTc analysis with the intent of characterizing QTc effects. [ABSTRACT FROM AUTHOR]

Postoperative nausea and vomiting (PONV) is a commonly encountered problem in surgical practice. It delays discharge from the post-anesthesia care unit, requires additional resources to treat, and may increase the morbidity in some patients. Many effective drugs are available to treat or prevent PONV, however many of these drugs have the potential to prolong the QTc on the electrocardiogram (EKG) and increase the risk of serious ventricular arrhythmias, in particular, torsade de pointes. The QTc prolongation may be a manifestation of a genetic mutation resulting in abnormal myocyte repolarization or it may be acquired and associated with the use of various medications, electrolyte disorders, and physiological conditions. Patients predisposed to QTc prolongation presenting for surgery constitute a challenging group, since many drugs commonly used for PONV management will put them at risk for perioperative serious arrhythmias. This is an important topic, and our mini-review is an attempt to highlight the problem, summarize the existing experience, and generate recommendations for safe management of PONV for patients, who are at increased risk of QTc prolongation and arrhythmias. Focused prospective studies will help to find definitive answers to the discussed problems and challenges and develop specific guidelines for clinical application.

BackgroundA secondary rise of intracellular Ca(2+) (Cai) and an upregulation of apamin-sensitive K(+) current (I(KAS)) are characteristic findings of failing ventricular myocytes. We hypothesize that apamin, a specific I(KAS) blocker, may induce torsades de pointes (TdP) ventricular arrhythmia from failing ventricles exhibiting secondary rises of Cai.ObjectiveTo test the hypothesis that small conductance Ca(2+) activated IKAS maintains repolarization reserve and prevents ventricular arrhythmia in a rabbit model of heart failure (HF).MethodsWe performed Langendorff perfusion and optical mapping studies in 7 hearts with pacing-induced HF and in 5 normal control rabbit hearts. Atrioventricular block was created by cryoablation to allow pacing at slow rates.ResultsThe left ventricular ejection fraction reduced from 69.1% [95% confidence interval 62.3%-76.0%] before pacing to 30.4% [26.8%-34.0%] (N = 7; P < .001) after pacing. The corrected QT interval in failing ventricles was 337 [313-360] ms at baseline and 410 [381-439] ms after applying 100 nmol/L of apamin (P = .01). Apamin induced early afterdepolarizations (EADs) in 6 ventricles, premature ventricular beats (PVBs) in 7 ventricles, and polymorphic ventricular tachycardia consistent with TdP in 4 ventricles. The earliest activation site of EADs and PVBs always occurred at the site with long action potential duration and large amplitude of the secondary rises of Ca(i). Apamin induced secondary rises of Ca(i) in 1 nonfailing ventricle, but no EAD or TdP were observed.ConclusionsIn HF ventricles, apamin induces EADs, PVBs, and TdP from areas with secondary rises of Ca(i). I(KAS) is important in maintaining repolarization reserve and preventing TdP in HF ventricles.

BackgroundAbnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine.ObjectiveTo determine whether the QT interval, a marker of ventricular repolarization, could be used to predict incident AF.MethodsWe examined a prolonged QT interval corrected by using the Framingham formula (QT(Fram)) as a predictor of incident AF in the Atherosclerosis Risk in Communities (ARIC) study. The Cardiovascular Health Study (CHS) and Health, Aging, and Body Composition (ABC) study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by using other formulas.ResultsAmong 14,538 ARIC study participants, a prolonged QT(Fram) predicted a roughly 2-fold increased risk of AF (hazard ratio [HR] 2.05; 95% confidence interval [CI] 1.42-2.96; P < .001). No substantive attenuation was observed after adjustment for age, race, sex, study center, body mass index, hypertension, diabetes, coronary disease, and heart failure. The findings were validated in Cardiovascular Health Study and Health, Aging, and Body Composition study and were similar across various QT correction methods. Also in the ARIC study, each 10-ms increase in QT(Fram) was associated with an increased unadjusted (HR 1.14; 95% CI 1.10-1.17; P < .001) and adjusted (HR 1.11; 95% CI 1.07-1.14; P < .001) risk of AF. Findings regarding a short QT interval were inconsistent across cohorts.ConclusionsA prolonged QT interval is associated with an increased risk of incident AF.

Aims: We aimed to examine whether routine pulmonary vein isolation (PVI) induces significant ventricular repolarization changes as suggested earlier.Methods and Results: Five-minute electrocardiograms were recorded at hospital's admission (T-1d), 1 day after the PVI-procedure (T+1d) and at 3 months post-procedure (T+3m) from a registry of consecutive atrial fibrillation (AF) patients scheduled for routine PVI with different PVI modalities (radiofrequency, cryo-ablation, and hybrid). Only patients who were in sinus rhythm at all three recordings (n = 117) were included. QT-intervals and QT-dispersion were evaluated with custom-made software and QTc was calculated using Bazett's, Fridericia's, Framingham's, and Hodges' formulas. Both QT- and RR-intervals were significantly shorter at T+1d (399 ± 37 and 870 ± 141 ms) and T+3m (407 ± 36 and 950 ± 140 ms) compared with baseline (417 ± 36 and 1025 ± 164 ms). There was no statistically significant within-subject difference in QTc Fridericia (T-1d 416 ± 28 ms, T+1d 419 ± 33 ms, and T+3m 414 ± 25 ms) and QT-dispersion (T-1d 18 ± 12 ms, T+1d 21 ± 19 ms, and T+3m 17 ± 12 ms) between the recordings. A multiple linear regression model with age, sex, AF type, ablation technique, first/re-do ablation, and AF recurrence to predict the change in QTc at T+3m with respect to QTc at T-1d did not reach significance which indicates that the change in QTc does not differ between all subgroups (age, sex, AF type, ablation technique, first/re-do ablation, and AF recurrence).Conclusion: Based on our data a routine PVI does not result in a prolongation of QTc in a real-world population. These findings, therefore, suggest that there is no need to intensify post-PVI QT-interval monitoring. [ABSTRACT FROM AUTHOR]

Glasdegib is a potent, selective oral inhibitor of the Hedgehog signaling pathway. This phase 1 double‐blind thorough QT study (NCT03162900) evaluated the effects of glasdegib on QTc interval. The study enrolled 36 healthy volunteers to receive a single dose of 150 mg glasdegib (representing a therapeutic dose), 300 mg glasdegib (representing a supratherapeutic dose), 400 mg moxifloxacin (positive control), or placebo under fasted conditions. The study demonstrated that therapeutic and supratherapeutic doses of glasdegib had no significant effect on QTc interval; the upper bound of the 2‐sided 90% confidence intervals (CIs) for all time‐matched least‐squares mean differences in QT interval corrected using Fridericia's formula (QTcF) between glasdegib and placebo was below the prespecified criterion of 20 milliseconds (Food and Drug Administration correspondence reviewed and accepted). Based on an exposure–response analysis, glasdegib was determined not to have a meaningful effect on heart rate (change in RR interval). The mean (90%CI) model‐derived baseline and placebo‐adjusted QTcF at the average maximum observed concentration values corresponding to therapeutic and supratherapeutic glasdegib doses was 7.3 milliseconds (6.5‐8.2 milliseconds) and 13.7 milliseconds (12.0‐15.5 milliseconds), respectively. Together these results demonstrated that following therapeutic and supratherapeutic glasdegib dosing, the change in QTc from baseline was well below the 20‐millisecond threshold of clinical concern in oncology. [ABSTRACT FROM AUTHOR]

Objective: Trigeminocardiac reflex is a reflex characterized by hypotension, bradycardia, gastric hypermotility or asystole that develops as a result of stimulation of the trigeminal nerve. In our retrospective study, in septorhinoplasty operations performed under general anesthesia, trigeminocardiac reflex development was investigated primarily during the periods where the reflex was surgically stimulated. Secondly, the effect of different inhalation anesthetic agents on the emergence of this reflex was investigated. Methods: Anesthesia notes and Datex Ohmeda icentral central monitor records of septorhinoplasty cases operated between 01 / January / 2016 - 30 / November / 2016 were retrospectively examined and detected through the Hospital Information Management System software. Induction, application of local anesthesia, surgical incision, initiation of incision suturing and 5 minutes after extubation were recorded from the records. It was determined that two different inhalation anesthetics were administered in 60 patients who met the criteria, and analyzes were performed in 2 separate groups as group sevoflurane and group desflurane, and the development of QT, QTc and Trigeminocardiac reflex was investigated. Results: Although there was no difference between the groups, when the basal values were compared with the other periods, it was found that the development of TKR and QT and QTc experts were mostly observed in the periods of local anesthesia, surgical incision and incision suturing. (p <0.001). Conclusions: We think that the inhalation anesthetic agents used mostly in the sevoflurane group play a facilitating role in the development of TKR, especially by creating a cumulative effect during periods when the trigeminal nerve is maximally stimulated. [ABSTRACT FROM AUTHOR]

Background: QTc prolongation is an adverse effect of COVID-19 therapies. The use of a handheld device in this scenario has not been addressed. Objectives: To evaluate the feasibility of QTc monitoring with a smart device in COVID-19 patients receiving QTc-interfering therapies. Methods: Prospective study of consecutive COVID-19 patients treated with hydroxychloroquine ± azithromycin ± lopinavir-ritonavir. ECG monitoring was performed with 12-lead ECG or with KardiaMobile-6L. Both registries were also sequentially obtained in a cohort of healthy patients. We evaluated differences in QTc in COVID-19 patients between three different monitoring strategies: 12-lead ECG at baseline and follow-up (A), 12-lead ECG at baseline and follow-up with the smart device (B), and fully monitored with handheld 6-lead ECG (group C). Time needed to obtain an ECG registry was also documented. Results: One hundred and eighty-two COVID-19 patients were included (A: 119(65.4%); B: 50(27.5%); C: 13(7.1%). QTc peak during hospitalization did significantly increase in all groups. No differences were observed between the three monitoring strategies in QTc prolongation (p = 0.864). In the control group, all but one ECG registry with the smart device allowed QTc measurement and mean QTc did not differ between both techniques (p = 0.612), displaying a moderate reliability (ICC 0.56 [0.19-0.76]). Time of ECG registry was significantly longer for the 12-lead ECG than for handheld device in both cohorts (p < 0.001). Conclusion: QTc monitoring with KardiaMobile-6L in COVID-19 patients was feasible. Time of ECG registration was significantly lower with the smart device, which may offer an important advantage for prevention of virus dissemination among healthcare providers. [ABSTRACT FROM AUTHOR]

Background: Inpatient monitoring is recommended for sotalol initiation., Objective: The purpose of this study was to assess the safety of outpatient sotalol commencement., Methods: This is a multicenter, retrospective, observational study of patients initiated on sotalol in an outpatient setting. Serial electrocardiogram monitoring at day 3, day 7, 1 month, and subsequently as clinically indicated was performed. Corrected QT (QTc) interval and clinical events were evaluated., Results: Between 2008 and 2023, 880 consecutive patients who were commenced on sotalol were evaluated. Indications were atrial fibrillation/flutter in 87.3% (n = 768), ventricular arrhythmias in 9.9% (n = 87), and other arrhythmias in 2.8% (n = 25). The daily dosage at initiation was 131.0 ± 53.2 mg/d. The QTc interval increased from baseline (431 ± 32 ms) to 444 ± 37 ms (day 3) and 440 ± 33 ms (day 7) after sotalol initiation ( P < .001). Within the first week, QTc prolongation led to the discontinuation of sotalol in 4 and dose reduction in 1. No ventricular arrhythmia, syncope, or death was observed during the first week. Dose reduction due to asymptomatic bradycardia occurred in 3 and discontinuation due to dyspnea in 3 within the first week. Overall, 1.1% developed QTc prolongation (>500 ms/>25% from baseline); 4 within 3 days, 1 within 1 week, 4 within 60 days, and 1 after >3 years. Discontinuation of sotalol due to other adverse effects occurred in 41 patients within the first month of therapy., Conclusion: Sotalol initiation in an outpatient setting with protocolized follow-up is safe, with no recorded sotalol-related mortality, ventricular arrhythmias, or syncope. There was a low incidence of significant QTc prolongation necessitating discontinuation within the first month of treatment. Importantly, we observed a small incidence of late QT prolongation, highlighting the need for vigilant outpatient surveillance of individuals on sotalol., Competing Interests: Dr Emami reports that the 10.13039/501100001786University of Adelaide has received on his behalf consulting fees from 10.13039/100004374Medtronic and 10.13039/100007497Biosense Webster. Dr Sanders reports having served on the advisory board of Medtronic, Abbott Medical, Boston Scientific, PaceMate, and CathRx. Dr Sanders reports that the 10.13039/501100001786University of Adelaide has received on his behalf lecture and/or consulting fees from Medtronic, Boston Scientific, and 10.13039/100000046Abbott Medical. Dr Sanders reports that the 10.13039/501100001786University of Adelaide has received on his behalf research funding from Medtronic, Abbott Medical, 10.13039/100008497Boston Scientific, and MicroPort. All other authors have no disclosures., (Crown Copyright © 2024 Published by Elsevier Inc. on behalf of Heart Rhythm Society.)

Background and Aims: Overweight and obesity have been found to exhibit a statistically significant increase in corrected QT interval (QTc), a major contributing factor to sudden death. However, the influence of widely used weight loss strategies including diet, exercise, anti-obesity drugs, and bariatric surgery on QTc remains inconsistent. Therefore, the present systematic review and meta-analysis aim to quantitatively analyse and evaluate the effect of weight loss on QTc in obese patients after diet control with exercise intervention and anti-obesity drugs, as well as bariatric surgery., Methods: Twenty randomised controlled trials (RCT) and observational studies were included in the meta-analysis on the effects of weight loss on QTc. The fixed-effects model was employed in the RCTs, and the random-effects model was employed due to the presence of statistical heterogeneity among observational studies. Subgroup analysis was conducted to understand the differences in distinct weight loss methods and follow-up time., Results: Overall, the QTc of people with obesity after weight loss was shorter than that before (mean difference (MD) = 21.97 ms, 95% confidence interval (CI) = 12.42, 31.52, p  < .0001). Subgroup analysis restricted to seven included studies whose intervention was diet control with exercise showed a decrease of QTc with statistical significance (MD = 9.35 ms, 95%CI = 2.56, 37.54, p  = .007). In the remaining 11 studies, bariatric surgery was the weight loss method. The results also showed a shortening of QTc after surgery, and the difference was statistically significant (MD = 29.04 ms, 95%CI = -16.46, 41.62, p  < .00001). A statistically significant difference in QTc shortening at 6 months compared to pre-operation values was further observed (MD = -31.01 ms, 95%CI = -2.89, -59.12, p  = .03). The shortening of QTc at 12 months of follow-up was also significantly different from that before surgery (MD = 36.47 ms, 95%CI = 14.17, 58.78, p  < .00001). Moreover, the differences became more pronounced as the follow-up time extended., Conclusions: We demonstrate that weight loss links to a shortened QTc, without considering the means of weight loss. Bariatric surgery has been found to result in a greater reduction in QTc.

Objective. This study determined the relationship between plasma adiponectin level and corrected QT interval (QTc) in smokers and non-smokers. Methodology. This cross-sectional analytical study was undertaken in 30 smokers and 30 non-smokers. Plasma adiponectin level was determined by enzyme-linked immunosorbent assay (ELISA). The QT interval was measured by routine 12-lead ECG with Lead II rhythm and QTc was calculated. Results. Mean plasma adiponectin level was significantly lower in smokers (27.89±15 μg/ml) than that of non-smokers (52.13±21.57μg/ml) (p

Women have higher risk for developing TdP in response to ventricular repolarization prolonging drugs. Hundreds of trials are administering chloroquine and hydroxychloroquine with/without azithromycin to COVID-19 patients. While an overall prolonged QTc has been reported in COVID-19 patients undergoing these treatments, the question on even higher QTc elevation risk in thousands of female COVID-19 patients undergoing these treatments remains unanswered. We therefore explore data reported and shared with us to evaluate safety and efficacy of antimalaria pharmacotherapies in female COVID-19 patients. Although we observed longer mean QTc intervals in female patients in 2 of the 3 cohorts reviewed, the sex disproportionality in COVID-19 hospitalizations precludes a clear sex mediated QTc interval elevation risk association in the female COVID-19 patients undergoing acute treatment regimens. Adoption of study designs that include observation of sex mediated differential triggering of cardiac electrical activity by these drugs is warranted.

The COVID-19 pandemic is an unprecedented challenge and will require novel therapeutic strategies. Affected patients are likely to be at risk of arrhythmia due to underlying comorbidities, polypharmacy and the disease process. Importantly, a number of the medications likely to receive significant use can themselves, particularly in combination, be pro-arrhythmic. Drug-induced prolongation of the QT interval is primarily caused by inhibition of the hERG potassium channel either directly and/or by impaired channel trafficking. Concurrent use of multiple hERG-blocking drugs may have a synergistic rather than additive effect which, in addition to any pre-existing polypharmacy, critical illness or electrolyte imbalance, may significantly increase the risk of arrhythmia and Torsades de Pointes. Knowledge of these risks will allow informed decisions regarding appropriate therapeutics and monitoring to keep our patients safe.

A multicenter-observational study was performed to assess the effectiveness of rac-methadone, levomethadone, and buprenorphine in opioid-dependent patients in polytherapy in Southern Italy. The primary endpoint was the reduction of urinary positivity to the substances and the maintaining doses. Patients (N = 266, age = 44.80 ± 5.65, male = 79.70%, female = 20.30%) have been recruited. At recruitment, 75% of them were on treatment with rac-methadone, levomethadone, and buprenorphine/naloxone. The patients were grouped into three clusters. The levomethadone patients of Cluster A (N patients = 211), after 180 days, showed stability in urinary methadone positivity, with a marked decrease in heroin −53 ± 4%, cannabinol’s −48 ± 2%, and cocaine −37 ± 6% positivity, with no differences between treatments. A lower QTcF value of 426 ± 8.4 ms was recorded in the levomethadone patients (delta = −19 ms) vs. rac-methadone, at significantly lower doses of levomethadone (−34%, −50.2% in males) (p < 0.05). The Cluster B data were collected from 37 patients, with a high prevalence of comorbidity infections (HIV/HCV/HPV), monitored for 21 months during COVID-19. High doses of levomethadone (58.33 ± 31.58 mg/day) were needed to stabilize those that were negative for opioids and cannabinoids, in contrast to the rac-methadone and buprenorphine/naloxone patients that showed positive toxicology. Eighteen patients of the Cluster C in double diagnosis (major depressive 38.90%, bipolar 27.78%, and schizophrenia 16.67%) were stabilized with high doses of racemate 97.5 ± 8 mg/day, 51.8 ± 5 mg/day of levomethadone (−46.8% vs. rac-methadone; −71% in men), and 2.5 ± 1 mg/day of buprenorphine/naloxone. Three patients in remission were treated with tapering doses of levomethadone. Significantly reduced QTcF values were recorded with levomethadone (delta −32 ms vs. rac-methadone) in the bipolar patients, as well as the schizophrenia patients in remission (delta −45.19 ms vs. rac-methadone). Our patients were safely stabilized. Levomethadone, compared to the racemate, contributes to reducing the illicit use, especially of opioids and cannabinoids at significantly lower doses with cardiovascular safety, which, in bipolar patients, is clinically significant.

Gianfranco Piccirillo,1 Federica Moscucci,1 Fabiola Mastropietri,1 Claudia Di Iorio,1 Marco Valerio Mariani,1 Marcella Fabietti,1 Gaetana M Stricchiola,1 Ilaria Parrotta,1 Gennaro Sardella,1 Massimo Mancone,1 Damiano Magrì2 1Department of Cardiovascular, Respiratory, Nephrological, Anesthesiologic, and Geriatric Sciences, Policlinico Umberto I, “La Sapienza” University of Rome, Rome, Italy; 2Department of Molecular and Clinical Medicine, S. Andrea Hospital, “Sapienza” University of Rome, Rome, Italy Objectives: To evaluate the predicative power of the electrical risk score (ERS), a noninvasive and inexpensive test obtained by means of a standard 12-lead electrocardiogram (ECG), in a cohort of elderly patients who had undergone transcatheter aortic valve replacement (TAVR).Methods: Survivors and non-survivors after TAVR at 1-year follow-up were compared in respect to the pre-procedural ERS as well as a number of other clinical and instrumental variables. ERS is composed of seven simple ECG markers: heart rate (>75 bpm); QRS duration (>110 ms); left ventricular hypertrophy (Sokolow–Lyon criteria); delayed QRS transition zone (≥ V4); frontal QRS-T angle (>90°); long QTBazett (>450 ms for men and >460 in women) or JTBazett (330 ms for men and >340 ms for women); and long Tpeak to Tend interval (Tp-e) (>89 ms). The trial was registered in ClinicalTrials.gov as NCT03145376.Results: A total of 40 patients were evaluated. During the follow-up, the all-cause mortality rate was 25% (ten patients) with 15% of cardiovascular death (six patients). The ERS was the strongest predictor of all-cause (odds ratio 3.73, 95% CI: 1.44–9.66, P

Jowita Biernawska,1 Joanna Solek-Pastuszka,1 Arkadiusz Kazimierczak,2 Krzysztof Safranow,3 Mariusz Kaczmarczyk,4 Malgorzata Zegan-Baranska,5 Maciej Zukowski,5 Katarzyna Kotfis5 1Department of Anesthesiology and Intensive Therapy, Pomeranian Medical University, Szczecin, Poland; 2Department of Angiology and Vascular Surgery, Pomeranian Medical University, Szczecin, Poland; 3Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Szczecin, Poland; 4Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, Szczecin, Poland; 5Department of Anesthesiology, Intensive Therapy and Acute Intoxications, Pomeranian Medical University, Szczecin, Poland Purpose: We aimed at assessing the predisposition of A-kinase anchoring protein 10 (AKAP10) polymorphism toward acquired repolarization disorders in high-risk vascular surgery patients. Patients and methods: One hundred adult patients (age =44–85 years), scheduled for an elective high-risk “open” vascular surgery procedure, were recruited. The electrocardiogram Holter monitor was used to assess repolarization stability from the beginning of the operation up to 24 hours afterward. The AKAP10 gene rs203462 polymorphism and cardiac complications were analyzed. Results: Repolarization disturbances defined as QT interval duration corrected for heart rate (QTc) interval prolongation >500 ms and QTc interval dispersion >65 ms were recorded in 46 patients. A model of multivariate logistic regression showed that only the presence of allele G of the AKAP10 polymorphism was an independent risk factor for repolarization disturbances in the perioperative period (odds ratio =14.35; 95% CI =4.65–44.23; p

Background: Cardiovascular and arrhythmic events have been reported in hospitalized COVID-19 patients. However, arrhythmia manifestations and treatment strategies used in these patients have not been well-described. We sought to better understand the cardiac arrhythmic manifestations and treatment strategies in hospitalized COVID-19 patients through a worldwide cross-sectional survey. Methods: The Heart Rhythm Society (HRS) sent an online survey (via SurveyMonkey) to electrophysiology (EP) professionals (physicians, scientists, and allied professionals) across the globe. The survey was active from March 27 to April 13, 2020. Results: A total of 1197 respondents completed the survey with 50% of respondents from outside the USA, representing 76 countries and 6 continents. Of respondents, 905 (76%) reported having COVID-19-positive patients in their hospital. Atrial fibrillation was the most commonly reported tachyarrhythmia whereas severe sinus bradycardia and complete heart block were the most common bradyarrhythmias. Ventricular tachycardia/ventricular fibrillation arrest and pulseless electrical activity were reported by 4.8% and 5.6% of respondents, respectively. There were 140 of 631 (22.2%) respondents who reported using anticoagulation therapy in all COVID-19-positive patients who did not otherwise have an indication. One hundred fifty-five of 498 (31%) reported regular use of hydroxychloroquine/chloroquine (HCQ) + azithromycin (AZM); concomitant use of AZM was more common in the USA. Sixty of 489 respondents (12.3%) reported having to discontinue therapy with HCQ + AZM due to significant QTc prolongation and 20 (4.1%) reported cases of Torsade de Pointes in patients on HCQ/chloroquine and AZM. Amiodarone was the most common antiarrhythmic drug used for ventricular arrhythmia management. Conclusions: In this global survey of > 1100 EP professionals regarding hospitalized COVID-19 patients, a variety of arrhythmic manifestations were observed, ranging from benign to potentially life-threatening. Observed adverse events related to use of HCQ + AZM included prolonged QTc requiring drug discontinuation as well as Torsade de Pointes. Large prospective studies to better define arrhythmic manifestations as well as the safety of treatment strategies in COVID-19 patients are warranted. [ABSTRACT FROM AUTHOR]

Objective: Prolonged T-peak to T-end (Tp-e), a ventricular repolarization parameter, has been related with ventricular arrhythmias (VAs). Novel electrocardiogram (ECG) parameters of ventricular repolarization have received considerable attention recently. In this study, we sought to investigate ventricular repolarization indexes such as the Tp-e and corrected Tp-e (Tp-ec) intervals, Tp-e/QT, Tp-e/QTc, and Tp-ec/QT ratios in patients with electrical injuries (EIs). Methods: Thirty-six patients diagnosed with EIs and 35 age- and sex-matched healthy control patients were included. Admission ECGs of the EI patients were compared with those of the healthy controls. QT and QTc intervals were measured, and the Tp-e and Tp-ec intervals, Tp-e/QT, Tp-ec/QT, and Tp-e/QTc ratios were then calculated from a 12-lead surface ECG. Results: The QT, Tp-e, Tp-e/QT, Tpe/QTc, Tp-ec/QT were not significantly different between the control group and the EI group (p > 0.05). However, the mean QTc interval was significantly higher in the EI group compared to the control group (412.81 ± 25.46 vs 396.31 ± 26.47 ms; p:0.009). Furthermore, the Tp-ec and Tp-ec/QT of the EI subgroup with elevated troponin levels significantly differed from those of the EI patients with normal troponin levels (p:0.033 and p:0.016, respectively). Conclusions: This retrospective study indicated that patients with EIs tend to have a prolonged QTc interval. Additionally, Tp-ec and Tp-ec/QT, which reportedly designate the tendency for VAs, were significantly higher in the EI patients with elevated troponin I levels than the EI patients with normal troponin levels, suggesting that patients with myocardial injury may be prone to VAs. [ABSTRACT FROM AUTHOR]