Prolonged QTc Interval Research Articles

Osimertinib-Related QTc Prolongation: Real-World Incidence and Impact of Drug Dosing on Recurrence Risk

Background: Osimertinib is associated with increased risk of QTc interval prolongation compared to other epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, real-world data on its incidence, risk factors, and association with drug dosing is limited. Methods: This retrospective study analysed data from 970 Chinese patients with EGFR-positive non-small cell lung cancer (NSCLC) who received osimertinib between 1 November 2017 and 18 November 2023. Patients underwent pre-osimertinib (baseline) and regular electrocardiogram (ECG) monitoring while on osimertinib. QTc prolongation was graded according to Common Terminology Criteria for Adverse Events guidelines version 5.0. Clinical outcomes of patients with grade 3 or above QTc prolongation were collated. Results: Out of 970 patients, 9 (0.9%) developed grade 3 QTc prolongation. Median onset time from drug initiation was 49 days (range 14 to 371). No patients experienced arrhythmic events (grade 4) or death (grade 5). Notably, baseline QTc was above 450 ms (grade 1 or 2) in 7 of them (78%), comparing to 21% (102 out of 497) in patients without grade 3 QTc prolongation (p<0.001). Rechallenging osimertinib at 80mg daily dose resulted in recurrent grade 3 QTc prolongation in 3 out of 4 patients, while only 1 out of 9 experienced recurrences with dose reduction. Conclusion: The real-world incidence of osimertinib-induced grade 3 QTc prolongation was similar to that reported in clinical trials. Baseline QTc prolongation may be a potential risk factor. Dose reduction mitigated recurrence risk, while rechallenging osimertinib at same dose conferred high recurrence risk.

Oxidative damage and cardiotoxicity induced by 2-aminobenzothiazole in zebrafish (Danio rerio)

There is limited information available on cardiovascular toxicity of 2-Aminobenzothiazole (NTH), a derivative of benzothiazole (BTH) commonly used in tire production, in aquatic organisms. In the present study, the zebrafish embryos were exposed to varying concentrations of NTH (0, 0.05, 0.5, and 5 mg/L) until adulthood and the potential cardiovascular toxicity was assessed. NTH exposure resulted in striking aberrations in cardiac development, including heart looping failure and interference with atrioventricular canal differentiation. RNA-sequencing analysis indicated that NTH causes oxidative damage to the heart via ferroptosis, leading to oxygen supply disruption, cardiac malformation, and ultimately, zebrafish death. Quantitative real-time polymerase chain reaction (qPCR) analysis demonstrated the dysregulation of genes associated with early heart development, contraction, and oxidative stress. Additionally, reactive oxygen species accumulation and glutathione/malondialdehyde levels changes suggested a potential link between cardiac developmental toxicity and oxidative stress. In adult zebrafish, NTH exposure led to ventricular enlargement, decreased heart rate, reduced blood flow, and prolonged RR, QRS, and QTc intervals. To the best of our knowledge, this study is the first to provide evidence of cardiac toxicity and the adverse effects of ontogenetic NTH exposure in zebrafish, revealing the underlying toxic mechanisms connected with oxidative stress damage. These findings may provide crucial insights into the environmental risks associated with NTH and other BTHs.

Hydroxychloroquine-azithromycin, doubase C, and QTc prolongation in congolese patients with COVID-19: Myth or reality?

BACKGROUND QTc interval prolongation with an increased risk of torsade de pointes (Tsd) has been described in coronavirus disease 2019 (COVID-19) patients treated with hydroxychloroquine (HCQ) and azithromycin (AZI) in Western countries. In the DR Congo, few studies have evaluated the safety of this association or proposed new molecules. AIM To determine the incidence of QTc prolongation and Tsd in COVID-19 patients treated with HCQ-AZIs vs doubase C (new molecule). METHODS In present randomized clinical trial, we have included patients with mild or moderate COVID-19 treated with either HCQ-AZI or doubase C. Electrocardiogram (ECG) changes on day 14 of randomization were determined based on pretreatment tracing. Prolonged QTc was defined as ≥ 500 ms on day 14 or an increase of ≥ 80 ms compared to pretreatment tracing. Patients with cardiac disease, those undergoing other treatments likely to prolong QTc, and those with disturbed ECG tracings were excluded from the study. RESULTS The study included 258 patients (mean age 41 ± 15 years; 52% men; 3.4% diabetics, 11.1% hypertensive). Mild and moderate COVID-19 were found in 93.5% and 6.5% of patients, respectively. At baseline, all patients had normal sinus rhythm, a mean heart rate 78 ± 13/min, mean PR space 170 ± 28 ms, mean QRS 76 ± 13 ms, and mean QTc 405 ± 30 ms. No complaints suggesting cardiac involvement were reported during or after treatment. Only four patients (1.5%) experienced QTc interval prolongation beyond 500 ms. Similarly, only five patients (1.9%) had an increase in the QTc interval of more than 80 ms. QTc prolongation was more significant in younger patients, those with high viral load at baseline, and those receiving HCQ-AZI (P &lt; 0.05). None of the patients developed Tsd. CONCLUSION QTc prolongation without Tsd was observed at a lower frequency in patients treated with HCQ-AZI vs doubase C. The absence of comorbidities and concurrent use of other products that are likely to cause arrhythmia may explain our results.

Impact of Azithromycin on the Predisposition to Cardiac Arrhythmias in Adult Patients: A Systematic Review

Background: Azithromycin is a macrolide antibiotic that can lead to QT interval prolongation, which may trigger ventricular tachycardia, also known as torsades de pointes (TdP), the most common cardiac arrhythmia associated with these drugs. All macrolides are linked to QTc interval prolongation, with apparently higher risk with erythromycin and clarithromycin compared to azithromycin. Macrolides can extend QT and QTc intervals and cause cardiac arrhythmias, including TdP, ventricular tachycardia, and ventricular fibrillation, through their affinity for binding to the delayed rectifier potassium channel, IKr, inducing QT prolongation and risk of TdP. However, it is crucial to assess the risk-benefit ratio of prescribing azithromycin, especially in patients with preexisting cardiovascular disease or taking concomitant medications that prolong the QT interval. Objectives: The aim of this study is to determine whether azithromycin is genuinely associated with the occurrence of ventricular arrhythmias in adult patients. Materials and Methods: This systematic review is based on meticulous searching across Medline and Google Scholar databases, analysis of publications, and synthesis of available evidence regarding the risk of arrhythmias with the use of azithromycin. Results: We reviewed 6 articles that met the criteria, including 20.510.653 patients and 66 articles. While some studies suggest an increased risk of ventricular arrhythmias in certain subgroups of patients, others have not found a significant association between azithromycin and these arrhythmias. These discrepancies could be attributed to differences in the definition of arrhythmias, the duration of follow-up, or the characteristics of the groups of patients evaluated. The results point toward the need for a more thorough risk assessment before initiating this antibiotic in adult patients, especially those with known cardiovascular risk factors or those with a history of heart disease. Several risk factors, such as hypokalemia, pre-existing heart conditions, and concomitant use of other QT-prolonging medications, have been identified as increasing vulnerability to macrolide-induced arrhythmias. Conclusion: The results of the systematic review and cohort studies analyzed consistently suggest an association between the use of azithromycin and an increased risk of developing ventricular arrhythmias. This risk appears to be most evident in the elderly, with different studies showing variations in the magnitude of the risk. It is crucial to evaluate the risks and benefits of these antibiotics in each clinical situation, considering the information provided by observational studies and systematic reviews

Treatment discontinuation due to toxicity for patients with acute myeloid leukemia (AML) treated on SWOG S1203.

6529 Background: Curative-intent therapy for patients with newly diagnosed AML centers on the use of cytarabine as part of an intensive multi-drug induction regimen. Treatment-related toxicity may lead to patients stopping treatment, despite the considerable risk of inadequately treated AML. We compared rates of protocol therapy discontinuation due to adverse events (AEs) in either of two standard induction regimens (7+3 or high dose cytarabine + idarubicin, IA) on the S1203 study (Garcia-Manero; Leukemia 2023). Methods: S1203 was a randomized study of patients &lt;60 years old with newly diagnosed AML. Patients were required to have performance status (PS) &lt;3, ejection fraction &gt;45%, and no prolonged QTc interval or known cardiac disease. There were no exclusion criteria for kidney or liver function. On the 7+3 induction arm, subjects received daunorubicin 90 mg/m2 IV daily days 1-3 with continuous infusion cytarabine 100 mg/m2 daily days 1-7. On the IA arm, subjects received idarubicin 12 mg/m2 daily days 1-3 with continuous infusion cytarabine 1.5 g/m2 daily days 1-4. Toxicities were assessed per the Common Terminology Criteria for Adverse Events version 4.0. Rates of discontinuation were compared using Fisher’s exact test. Results: From 4/2013-11/2015, 522 subjects were randomized (261 to each arm). Treatment discontinuation due to either death or toxicity occurred in 8 vs 22 patients on 7+3 vs IA respectively (p=0.014). During induction, 0 patients on the 7+3 arm discontinued treatment due to toxicity versus 4 patients on the IA arm (0% vs 2%; p=0.12). Toxicities leading to treatment discontinuation on the IA arm included congestive heart failure (n=2, one with concurrent arrhythmia), acute kidney injury (n=1), and hypotension complicated by stroke and cardiac arrest (n=1). Two of the 4 patients who discontinued treatment due to toxicity on IA achieved a complete remission after their first cycle. For patients with PS 2-3 (n=40 on 7+3, n=27 on IA), rates of grade 3-5 AEs were 85% vs 86% and rates of grade 5 AEs were 0% vs 11% (p=0.065). Conclusions: 7+3 was well tolerated. Excluding patients from S1203 with PS 2-3 or decreased hepatic/renal function would not have prevented treatment-related toxicity. The low rate of protocol therapy discontinuation due to toxicity suggests that eligibility criteria for clinical trials could be further broadened to improve patient access. Clinical trial information: NCT0180233 . [Table: see text]

Cerebral Ischemia and Reperfusion-Induced Changes in Left Ventricular Function and Electrocardiogram in Mice

Background: Stroke may produce functional and electrical heart disturbances. The underlying characteristics and mechanisms have not been fully elucidated. Objectives: To evaluate whether acute cerebral ischemia (I) and reperfusion (R) may cause cardiac dysfunction and electrocardiographic alterations in an experimental mice model. Methods: Male mice that underwent cerebral ischemia and reperfusion (I/R) were evaluated by electrocardiography (ECG) and echocardiography. Heart rate, corrected QT (QTc) interval, T-wave peak to T-wave end (Tp-Te) interval, left ventricular ejection fraction (LVEF), shortening fraction (SF) and isovolumetric relaxation time (IVRT) were analyzed. Cerebral infarct size was calculated, and neurological deficit was assessed with the Longa scale. Results: Twenty-four hours after R, a statistically significant decrease in LVEF (I/R: 66.5±1.5% vs. sham: 74.3±0.9%; p=0.002) and in SF (I/R: 42.9±1.7% vs sham: 52.3±1.7%; p=0.004) was observed. QTc interval prolongation was observed during I/R (baseline: 125.1±4.3 ms; 60 min after I: 143.8±5.2 ms; 24 h after R: 170.3±5.8 ms; p=0.002). Tp-Te interval was not prolonged during I (baseline: 25.9±1.3 ms vs. 60 min after I: 23.8±1.4 ms; p=0.999) but it was prolonged during R (24 h after R: 32.0±2.3 ms; p=0.049). Cerebral infarct size was 34.9±2.5% and survival in the I/R group was 43.3%. Conclusion: Acute cerebral ischemia induces mild left ventricular dysfunction and disturbances in ventricular repolarization which intensify within the first 24 hours after reperfusion.

Concentration-QTc and cardiac safety analysis of single and multiple zavegepant nasal spray doses in healthy participants to support approval.

Zavegepant is a novel gepant administered as a nasal spray approved in the United States at a 10 mg dose for the acute treatment of migraine with or without aura in adults. The cardiovascular safety of zavegepant nasal spray was assessed in both single-ascending dose (SAD) and multiple-ascending dose (MAD) studies in healthy participants. The SAD study included 72 participants (54 active/18 placebo) who received 0.1-40 mg zavegepant or placebo. The MAD study included 72 participants (56 active/16 placebo) who received 5-40 mg zavegepant or placebo for 1-14 days. Plasma zavegepant pharmacokinetics and electrocardiographic (ECG) parameters (Fridericia-corrected QT interval [QTcF], heart rate, PR interval, ventricular depolarization [QRS], T-wave morphology, and U-wave presence) were analyzed pre- and post-zavegepant administration. Using pooled data from the SAD and MAD studies, the relationship between time-matched plasma zavegepant concentrations and QTc interval was assessed using a linear mixed-effects model to evaluate the potential for QTc interval prolongation. Results showed that single and multiple doses of zavegepant had no significant impact on ECG parameters versus placebo, and there was no concentration-dependent effect on QTcF interval. The estimated slope of the plasma zavegepant concentration-QTcF model was -0.053 ms per ng/mL with a 90% confidence interval of -0.0955 to -0.0110 (p = 0.0415), which is not considered clinically meaningful. At doses up to four times the recommended daily dose, zavegepant does not prolong the QT interval to any clinically relevant extent.

Evaluating adherence to ECG monitoring protocols for methadone patients in primary care.

Opioid Agonist Treatment (OAT) is the gold standard for managing Opioid Use Disorder (OUD). It is highly effective at reducing all-cause mortality and drug-related harms. Prescribing OAT, particularly methadone, is becoming increasingly complex as Scotland's OUD population ages. Older patients, with increased polypharmacy and multimorbidity, are more susceptible to QTc interval prolongation associated with methadone use. Therefore, adherence to ECG monitoring guidelines for patients prescribed methadone is crucial, though insights from substance use services indicate suboptimal compliance. Medically Assisted Treatment guidelines established by the Scottish Government advocate for shared care agreements, thus transferring OAT prescribing responsibilities to primary care. Understanding ECG monitoring guideline implementation in non-specialist services is vital for developing safe OAT services in primary care. This audit assessed adherence to NICE guidelines for ECG monitoring in OUD patients prescribed methadone in a Scottish primary care practice. The notes of patients prescribed methadone were assessed using NICE criteria to determine eligibility for ECG monitoring. Eligible patients' medical records were reviewed to identify previous ECG investigations. Of 21 patients prescribed methadone, 16 qualified for ECG monitoring. Only 25% of eligible patients received ECG monitoring per NICE guideline, meaning 75% did not. These findings highlight that the issue of poor compliance with ECG monitoring guidelines is not limited to specialist services, but also affects primary care. Further exploration of barriers to guideline implementation is essential. Perhaps more resources are needed to integrate OAT services into primary care, which has taken on increased responsibilities without corresponding investment.

Early Screening for Long QT Syndrome and Cardiac Anomalies in Infants: A Comprehensive Study.

(1) Background: Sudden Infant Death Syndrome (SIDS) represents sudden and unexplained deaths during the sleep of infants under one year of age, despite thorough investigation. Screening for a prolonged QTc interval, a marker for Long QT Syndrome (LQTS), should be conducted on all newborns to reduce the incidence of SIDS. Neonatal electrocardiograms (ECGs) could identify congenital heart defects (CHDs) early, especially those not detected at birth. Infants with prolonged QTc intervals typically undergo genetic analysis for Long QT Syndrome. (2) Methods: The study involved infants aged 20-40 days, born with no apparent clinical signs of heart disease, with initial ECG screening. Infants with prenatal diagnoses or signs/symptoms of CHDs identified immediately after birth, as well as infants who had previously had an ECG or echocardiogram for other medical reasons, were excluded from the study. We used statistical software (SPSS version 22.0) to analyze the data. (3) Results: Of the 42,200 infants involved, 2245 were enrolled, with 39.9% being males. Following this initial screening, 164 children (37.8% males) with prolonged QTc intervals underwent further evaluation. Out of these 164 children, 27 children were confirmed to have LQTS. However, only 18 children were finally investigated for genetic mutations, and mutations were identified in 11 tests. The most common mutations were LQT1 (54.5%), LQT2 (36.4%), and LQT3 (1 patient). Treatment options included propranolol (39.8%), nadolol (22.2%), inderal (11.1%), metoprolol (11.1%), and no treatment (16.7%). The most common abnormalities were focal right bundle branch block (54.5%), left axis deviation (9.2%), and nonspecific ventricular repolarization abnormalities (7.1%). Multiple anomalies were found in 0.47% of children with focal right bundle branch block. Structural abnormalities were associated with specific features in 267 patients (11.9%), primarily isolated patent foramen ovale (PFO) at 61.4%. (4) Conclusions: This screening approach has demonstrated effectiveness in the early identification of LQTS and other cardiac rhythm anomalies, with additional identification of mutations and/or prolonged QTc intervals in family members. Identifying other ECG abnormalities and congenital heart malformations further enhances the benefits of the screening.

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.

Genetic characterization of drug-induced long QT syndrome in a large prospective cohort

Abstract Introduction Drug-induced long QT syndrome (DI-LQTS) is a clinical entity with a poorly defined etiopathogenesis. Purpose The objective of the study was to determine the genetic basis of a prospective cohort of patients with DI-LQTS in the setting of a tertiary hospital center. Methods Prospective observational study with consecutive inclusion of patients with the diagnosis of DI-LQTS according to standard criteria, in a tertiary hospital, between 2018 and 2022. A genetic study was performed through massive DNA sequencing to identify variants in known genes associated with cardiopathy, arrhythmogenic and cardiomyopathy. Results 86 patients (age 65±15 years, 59% men) were included. The mean corrected QT interval (QTc) of the entire cohort was 543±56 ms. The drugs associated with QTc interval prolongation were: psychotropics 51%, antiarrhythmics 38%, anesthetics 30%, antibiotics 16%, antineoplastics 5%, others 4%. Twenty-one patients (24%) presented with ventricular arrhythmias at the time of drug-induced QTc prolongation: 10 (12%) ventricular fibrillation, 7 (8%) sustained ventricular tachycardia, 3 (3%) non-sustained ventricular tachycardia, 1 (1%) frequent ventricular premature beats. Genetic information was obtained in 83 (97%) patients. 17 pathogenic mutations associated with heart disease were identified in 15 (18%) patients: 4 (5%) patients with 5 mutations in ion channel genes (KCNE1, KCNE1B, KCNH2, RYR1, RYR2), and 12 (14%) patients with 12 mutations in genes associated with cardiomyopathy (NF1, PKD2, ABCC6, TTN, FHOD3, MYO6, COL11A1, CCDC40, CRELD1, COL4A1). Two patients had 2 pathogenic mutations each, one of them with both mutations associated with channelopathy, and another with a mutation associated with channelopathy and a second mutation related to cardiomyopathy. Only 1 patient carrying a pathogenic mutation related to cardiomyopathy had a clear phenotype, while in 3 carrier patients there was a history of transient systolic dysfunction, 2 due to tachycardiocardiopathy and 1 due to peripartum cardiomyopathy. The identification of a pathogenic mutation was not related to significant differences in QTc interval prolongation (544±63 vs 542±55 ms) or risk of ventricular arrhythmias (26% vs 24%). Conclusions The genetic basis of drug-induced long QT syndrome is essentially different from that of the congenital form of the disease. The identification of pathogenic mutations in genes associated with cardiomyopathy is relatively frequent, while those associated with ion channel genes are uncommon.

Injection of luteinizing hormone or human chorionic gonadotropin increases calcium excretion and serum PTH in males

Animal and human studies have suggested that sex steroids have calciotropic actions, and it has been proposed that follicle-stimulating hormone (FSH) may exert direct effects on bone. Here, we demonstrate the expression of the receptor for Luteinizing hormone (LH) and human choriogonadotropin (hCG), LHCGR, in human kidney tissue, suggesting a potential influence on calcium homeostasis. To investigate the role of LHCGR agonist on calcium homeostasis in vivo, we conducted studies in male mice and human subjects. Male mice were treated with luteinizing hormone (LH), and human extrapolation was achieved by injecting 5000 IU hCG once to healthy men or men with hypergonadotropic or hypogonadotropic hypogonadism. In mice, LH treatment significantly increased urinary calcium excretion and induced a secondary increase in serum parathyroid hormone (PTH). Similarly, hCG treatment in healthy men led to a significant increase in urinary calcium excretion, serum PTH levels, and 1,25 (OH)2D3, while calcitonin, and albumin levels were reduced, possibly to avoid development of persistent hypocalcemia. Still, the rapid initial decline in ionized calcium coincided with a significant prolongation of the cardiac QTc-interval that normalized over time. The observed effects may be attributed to LH/hCG-receptor (LHCGR) activation, considering the presence of LHCGR expression in human kidney tissue, and the increase in sex steroids occurred several hours after the changes in calcium homeostasis. Our translational study shed light on the intricate relationship between gonadotropins, sex hormones and calcium, suggesting that LHCGR may be influencing calcium homeostasis directly or indirectly.

#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.

Handgrip strength test for the diagnosis of long QT syndrome

Long QT syndrome (LQTS) assessment is based on the QT/ÖRR equation (the so-called Bazett's formula) and calculating the corrected QT (QTc). However, this formula reliably estimates the QT interval in the heart rate range (HR) of 60-90 bpm, which makes it difficult to diagnose LQTS in patients with sinus bradycardia, typical of this disease.Aim. To improve the LQTS diagnosis in patients with sinus bradycardia using the handgrip strength test.Material and methods. A total of 188 patients aged 5-53 years (16 [13;17]) were examined: group I — 40 healthy children aged 9-17 years (14 [12;16]); group II — 98 athletes with sinus bradycardia &lt;60 bpm aged 16 [16;17] years; group III — 50 patients with LQTS aged 5-53 years (12 [10;16]). The handgrip strength test consisted of regular rhythmic compression of a hand expander with a resistance of 20 kg until the heart rate increased &gt;60 bpm. The patients had an electrocardiogram recorded twice before and after the handgrip test. Heart rate, QT and QTc intervals were analyzed.Results. In all groups, after using the expander, there was a significant increase in heart rate, QT interval shortening and QTc interval prolongation. QTc interval prolongation after the handgrip test &gt;460 ms was a highly sensitive marker of LQTS (Se 96%, Sp 60%).Conclusion. Proposed handgrip test for sinus bradycardia makes it possible to increase heart rate, which ensures a more correct use of the Bazett's formula for assessing the corrected QT interval (QTc). QTc interval prolongation over 460 ms after the handgrip test is a highly sensitive additional marker for identifying patients with LQTS.

Prevalence, Attributes, and Risk Factors of QT-Interval-Prolonging Drugs and Potential Drug-Drug Interactions in Cancer Patients: A Prospective Study in a Tertiary Care Hospital.

Introduction Cancer chemotherapy regimens include multiple classes of adjuvant drugs as supportive therapy. Because of the concurrent intake of other drugs (like antiemetics, antidepressants, analgesics, and antimicrobials), there is a heightened risk for possible QT interval prolongation. There is a dearth of evidence in the literature regarding the usage of QT-prolonging anticancer drugs and associated risk factors that have the propensity to prolong QT interval. The purpose was to explore the extent of the use of QT-interval-prolonging drugs and potential QT-prolonging drug-drug interactions (QT-DDIs) in cancer patients attending OPD in a tertiary-care hospital. Methods This was a hospital-based, cross-sectional, observational study. Risk stratification of QT-prolonging drugs for torsades de pointes (TdP) was done by the Arizona Center for Education and Research on Therapeutics (AzCERT)/CredibleMeds-lists, and potential QT-DDIs were determined with four online DDI-checker-software. Results In 1331 cancer patients, the overall prevalence of potential QT-prolonging drug utilization was 97.3%. Ondansetron, pantoprazole, domperidone, and olanzapine were the most frequent QT-prolonging drugs in cancer patients. The top six antineoplastics with potential QT-prolongingand torsadogenic actions were capecitabine, oxaliplatin, imatinib, bortezomib, 5-fluorouracil, and bendamustine. Evidence-based pragmatic QTc interval prolongation risk assessment tools are imperative for cancer patients. Conclusion This study revealed a high prevalence of QT-prolonging drugs and QT-DDIs among cancer patients who are treated with anticancer and non-anticancer drugs. As a result, it's critical to take precautions, stay vigilant, and avoid QT-prolongingin clinical situations. Evidence-based pragmatic QTc interval prolongation risk assessment tools are needed for cancer patients.

A look into prolonged Qtc Interval in Patients undergoing Long-Term Hemodialysis at Ibn Sina Hospital, Khartoum, Sudan - 2020

A look into prolonged Qtc Interval in Patients undergoing Long-Term Hemodialysis at Ibn Sina Hospital, Khartoum, Sudan - 2020

Preclinical evaluation of combined therapy with amiodarone and low-dose benznidazole in a mouse model of chronic Trypanosoma cruzi infection

Chagasic chronic cardiomyopathy (CCC) is the primary clinical manifestation of Chagas disease (CD), caused by Trypanosoma cruzi. Current therapeutic options for CD are limited to benznidazole (Bz) and nifurtimox. Amiodarone (AMD) has emerged as most effective drug for treating the arrhythmic form of CCC. To address the effects of Bz and AMD we used a preclinical model of CCC. Female C57BL/6 mice were infected with T. cruzi and subjected to oral treatment for 30 consecutive days, either as monotherapy or in combination. AMD in monotherapy decreased the prolonged QTc interval, the incidence of atrioventricular conduction disorders and cardiac hypertrophy. However, AMD monotherapy did not impact parasitemia, parasite load, TNF concentration and production of reactive oxygen species (ROS) in cardiac tissue. Alike Bz therapy, the combination of Bz and AMD (Bz/AMD), improved cardiac electric abnormalities detected T. cruzi-infected mice such as decrease in heart rates, enlargement of PR and QTc intervals and increased incidence of atrioventricular block and sinus arrhythmia. Further, Bz/AMD therapy ameliorated the ventricular function and reduced parasite burden in the cardiac tissue and parasitemia to a degree comparable to Bz monotherapy. Importantly, Bz/AMD treatment efficiently reduced TNF concentration in the cardiac tissue and plasma and had beneficial effects on immunological abnormalities. Moreover, in the cardiac tissue Bz/AMD therapy reduced fibronectin and collagen deposition, mitochondrial damage and production of ROS, and improved sarcomeric and gap junction integrity. Our study underlines the potential of the Bz/AMD therapy, as we have shown that combination increased efficacy in the treatment of CCC.

Electrocardiographic Changes and Their Association With Disease Severity in Adults With Sickle Cell Anemia at a Tertiary Care Center: A Cross-Sectional Study.

Introduction Sickle cell anemia (SCA), a severe hematological disorder, is characterized by the presence of sickle-shaped erythrocytes that obstruct capillaries and restrict blood flow. This pathophysiology not only promotes systemic complications but may also influence cardiac function. Cardiac complications are a leading cause of mortality in SCA patients, yet the specific electrocardiographic (ECG) changes associated with disease severity are not thoroughly understood. This cross-sectional study aimed to explore ECG abnormalities in adults with SCA and correlate these findings with disease severity. Methods An observational cross-sectional study was conducted over 18 months, from January 2022 to June 2023, among 140 SCA patients at the Sickle Cell OPD of All India Institute of Medical Sciences, Raipur, Raipur, India. Steady-state SCA (HbS >50%) patients screened by high-performance liquid chromatography were enrolled. A history, physical examination, complete blood count, and ECG were done for all cases. The disease severity score was calculated using the Adegoke and Kuti severity scores, and their association with various ECG changes was studied. The chi-square test (Fisher's exact test, wherever applicable) was used for comparing the proportion. The correlation was done using the Pearson correlation coefficient or Spearman's rho. Results Out of 140 patients, the mean age of the study participants was 26 ± 6 years. More than half of the cases (80; 57%) fall under the 18-27 age group, with a male-to-female ratio of 4:3. A total of 99 (70.7%) of the participants had mild disease, and 41 (29.3%) had moderate disease. The QT interval was significantly higher among patients with mild disease compared to those with moderate disease (p-value: <0.01). QTc dispersion and prolonged QTc interval were significantly higher among patients with moderate disease compared to mild disease (p-value <0.01, 0.04, respectively). Sinus tachycardia and right ventricular hypertrophy with p-pulmonale were significantly higher in moderate severity (p < 0.01). A significant positive correlation was observed between QTc dispersion, P-wave dispersion, and severity (r: 0.19, 0.17; p-value: 0.02, 0.04, respectively). Conclusion As the disease severity progressed, the ECG changes studied had a higher distribution and significance. ECG is a readily and widely accessible investigation that can be used to screen all SCA patients for early recognition of various underlying cardiac complications.

Congenital Long QT Syndrome in Children and Adolescents: A General Overview.

Congenital long QT syndrome (LQTS) represents a disorder of myocardial repolarization characterized by a prolongation of QTc interval on ECG, which can degenerate into fast polymorphic ventricular arrhythmias. The typical symptoms of LQTS are syncope and palpitations, mainly triggered by adrenergic stimuli, but it can also manifest with cardiac arrest. At least 17 genotypes have been associated with LQTS, with a specific genotype-phenotype relationship described for the three most common subtypes (LQTS1, -2, and -3). β-Blockers are the first-line therapy for LQTS, even if the choice of the appropriate patients needing to be treated may be challenging. In specific cases, interventional measures, such as an implantable cardioverter-defibrillator (ICD) or left cardiac sympathetic denervation (LCSD), are useful. The aim of this review is to highlight the current state-of-the-art knowledge on LQTS, providing an updated picture of possible diagnostic algorithms and therapeutic management.

Comparison of QTc interval changes in drug-resistant tuberculosis patients on delamanid-containing regimens versus shorter treatment regimens.

Delamanid (DLM) is a relatively new drug for drug-resistant tuberculosis (DR-TB) that has been used in Indonesia since 2019 despite its limited safety data. DLM is known to inhibit hERG potassium channel with the potential to cause QT prolongation which eventually leads to Torsades de pointes (TdP). This study aims to analyse the changes of QTc interval in DR-TB patients on DLM regimen compared to shorter treatment regimens (STR). A retrospective cohort was implemented on secondary data obtained from two participating hospitals. The QTc interval and the changes in QTc interval from baseline (ΔQTc) were assessed every 4 weeks for 24 weeks. The maximum increased of QTc interval and ΔQTc interval were smaller in the DLM group with mean difference of 18,6 (95%CI 0.3 to 37.5) and 31.6 milliseconds (95%CI 14.1 to 49.1) respectively. The proportion of QTc interval prolongation in DLM group were smaller than STR group (RR=0.62; 95%CI 0.42 to 0.93). This study has shown that DLM regimens are less likely to increase QTc interval compared to STR. However, close monitoring of the risk of QT interval prolongation needs to be carried out upon the use of QT interval prolonging antituberculoid drugs.