Search Results (17)

Background: Prolongation of the QT interval is directly related to the risk of ventricular arrhythmias and sudden cardiac death. Age, comorbidities, and treatment schemes have been shown to influence its prolongation and may also significantly affect the course of SARS-CoV-2 infection. Fluoroquinolones, widely used during the COVID-19 pandemic, are known for their ability to prolong the QT interval. Risk of ventricular arrhythmias has also been reported in patients with infectious diseases, and this risk may have been associated with high levels of interleukin-6 (IL-6). Purpose: The aim of this study is to evaluate the effect of levofloxacin on the corrected QT interval in patients with COVID-19, as well as to identify sociodemographic, clinical, and biochemical parameters associated with QTc interval prolongation among patients with COVID-19. Patients and Methods: The medical records of 93 patients hospitalized for COVID-19 were retrospectively analyzed, focusing on the presence of comorbidities and treatment with levofloxacin. Selected sociodemographic, clinical, and biochemical parameters were then statistically analyzed, with emphasis on their effect on the corrected QTc interval. The QTc interval was calculated according to the Bazett formula. Results: Levofloxacin use was not significantly associated with QTc interval. Statistical analysis identified creatinine, heart failure and atrial fibrillation as significant predictors of QTc interval prolongation. The trends towards QTc interval prolongation observed with hypokalaemia and hypertension suggest that these factors may also contribute to QTc interval variability and should be taken into account when assessing arrhythmia risk. Conclusions: Our retrospective study indicates that QTc prolongation results from the interplay of multiple factors. Full article

Background: The study aimed to compare the prognostic importance of the heart rate (HR) and QT—corrected (QTc) according to Fridericia, Framingham, and Bazett with respect to all-cause mortality in a large non-selected population. Methods: The analysis of digital electrocardiograms archived from 2008 to 2022 in the metropolitan area of Modena, Italy, was carried out. The population under study was divided into three groups based on age, and survival analysis was performed. Results: 131,627 patients were enrolled and, during the follow-up (mean 1641.4 days), all-cause mortality was 8.9%. Both HR and QTc were associated with mortality. All-cause mortality significantly increased with HR values greater than 81 BPM and QTc values greater than 440 msec in young subjects and 455 msec in old subjects (values of the 75th percentiles/optimal operating point). A Cox analysis confirmed the better prognostic value of Bazett’s QTc and HR in the whole population and in the three age-groups. Conclusion: Bazett’s method performed better than the others, but, unexpectedly, the HR had the same or an even better correlation with all-cause mortality. Since the HR is simple and readily available, its evaluation should be improved. However, QTC and HR values are difficult to define, causing many confounding factors, and further population studies are required. Full article

The natural boundary is intuitively understood to be the line dividing the bed of a water body from the adjacent land. It is used in many jurisdictions to define the boundary of ownership between a land parcel and a state-owned watercourse. It is typically defined on the ground through observations by a professional surveyor. Predicting changes to the natural boundary has obvious utility (e.g., with climate change); however, its’ observational nature does not lend itself to such predictions. This paper uses a case study of a large lake to explore the relationship between shoreline morphology and hydrology, and the elevation of the natural boundary. Significant correlation was found between the natural boundary elevation and average wave power, but not with variables beach slope, sediment type, or presence of vegetation. Below 0.4 W/m of average wave power, the correlation with natural boundary elevation is very weak, suggesting a lower limit of influence. Two process-based methods for estimation of natural boundary change are proposed, one based on the observed statistical relationship between the average wave power and the natural boundary elevation, and another method based on detailed analytical modelling of bottom stress from breaking waves using the Xbeach software (v1.23). Both methods were used to estimate natural boundary change under a hypothetical change in water level regime due to proposed weir upgrades. While observational data are not available to support evaluation, both approaches predict similar changes to the natural boundary despite their significantly different basis. While the modelling approach requires significant analyst and computational effort, the parametric approach is comparatively efficient, making it practical to apply at high resolution over very large shorelines. Full article

Methadone is a chiral synthetic opioid primarily used to treat heroin and prescription-opioid addiction: the (R)-enantiomer (Levomethadone) activates the µ-opioid receptor more potently than the (S)-enantiomer, which is a more potent blocker of the hERG potassium channels, resulting in QTc prolongation. The purpose of this retrospective study was to assess the effect of methadone on the QTc interval and to investigate the benefits of Levomethadone. The electrocardiograms of 165 patients taking methadone at various dosages and for different periods of time were examined: the QTc value was manually measured and then adjusted using Bazett’s formula. Data analysis revealed a linear association between the dosage of methadone and QTc length; no correlation was found between the QTc value and gender, age, or duration of therapy. In total, 14% of the sample (23 patients) showed a prolongation of the QTc interval (>470 ms in males and >480 ms in females); 10 of the 23 patients with QTc elongation underwent a change of therapy from Methadone to Levomethadone—in 90% of these patients, a normalization in the QTc length was established. This study confirmed the role of methadone, specifically its dosage, in QTc prolongation and the efficiency of Levomethadone as an adequate therapeutic substitute in these circumstances. This study validates the importance of careful electrocardiographic monitoring in methadone-treated patients. Full article

The COVID-19 pandemic has highlighted an urgent need to discover and test new drugs to treat patients. Metal-based drugs are known to interact with DNA and/or a variety of proteins such as enzymes and transcription factors, some of which have been shown to exhibit anticancer and antimicrobial effects. BOLD-100 (sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)]dihydrate) is a novel ruthenium-based drug currently being evaluated in a Phase 1b/2a clinical trial for the treatment of advanced gastrointestinal cancer. Given that metal-based drugs are known to exhibit antimicrobial activities, we asked if BOLD-100 exhibits antiviral activity towards SARS-CoV-2. We demonstrated that BOLD-100 potently inhibits SARS-CoV-2 replication and cytopathic effects in vitro. An RNA sequencing analysis showed that BOLD-100 inhibits virus-induced transcriptional changes in infected cells. In addition, we showed that the antiviral activity of BOLD-100 is not specific for SARS-CoV-2, but also inhibits the replication of the evolutionarily divergent viruses Human Immunodeficiency Virus type 1 and Human Adenovirus type 5. This study identifies BOLD-100 as a potentially novel broad-acting antiviral drug. Full article

Background: Female gender, degree of QT prolongation, and genetic susceptibility are known risk factors for developing torsades de pointes (TdP) during high-grade atrioventricular block (HG-AVB). Our objective was to analyze the prevalence and clinical characteristics of patients presenting with TdP and AVB (TdP [+]) in comparison with non-TdP patients with AVB (TdP [−]). Methods: All the ECGs from patients prospectively admitted for AVB (2 to 1, HG, and complete) at the University Hospital of Nice were analyzed. Automated corrected QT (QTc), manual measurements of QT and JT intervals, and Tpeak-to-end were performed at the time of the most severe bradycardia. Results: From September 2020 to November 2021, 100 patients were admitted for HG-AVB. Among them, 17 patients with TdP were identified (8 men; 81 ± 10 years). No differences could be identified concerning automated QTc, manual QTc (Bazett correction), baseline QRS width, or mean left ventricular ejection fraction between the two groups. Potassium serum level on admission and mean number of QT-prolonging drugs per patient were not significantly different between the two groups, respectively: 4.34 ± 0.5 mmol/L in TdP [+] versus 4.52 ± 0.6 mmol/L (p = 0.33); and 0.6 ± 0.7 in TdP [+] versus 0.3 ± 0.5 (p = 0.15). In contrast, manual QTc_FR (Fridericia correction), JT (Fridericia correction), Tpeak-to-end, and Tpe/QT ratio were significantly increased in the TdP [+] group, respectively: 486 ± 70 ms versus 456 ± 53 ms (p = 0.04); 433 ± 98 ms versus 381 ± 80 ms (p = 0.02); 153 ± 57 ms versus 110 ± 40 ms (p < 0.001); and 0.27 ± 0.08 versus 0.22 ± 0.06 (p < 0.001). Conclusions: The incidence of TdP complicating acquired AVB was 17%. Longer QTc_FR, JT, and Tpeak-to-end were significantly increased in the case of TdP but also in the presence of permanent AVB during the hospitalization. Full article

BOLD-100 (sodium trans-[tetrachlorobis(1H indazole)ruthenate(III)]) is a ruthenium-based anticancer compound currently in clinical development. The identification of cancer types that show increased sensitivity towards BOLD-100 can lead to improved developmental strategies. Sensitivity profiling can also identify mechanisms of action that are pertinent for the bioactivity of complex therapeutics. Sensitivity to BOLD-100 was measured in a 319-cancer-cell line panel spanning 24 tissues. BOLD-100’s sensitivity profile showed variation across the tissue lineages, including increased response in esophageal, bladder, and hematologic cancers. Multiple cancers, including esophageal, bile duct and colon cancer, had higher relative response to BOLD-100 than to cisplatin. Response to BOLD-100 showed only moderate correlation to anticancer compounds in the Genomics of Drug Sensitivity in Cancer (GDSC) database, as well as no clear theme in bioactivity of correlated hits, suggesting that BOLD-100 may have a differentiated therapeutic profile. The genomic modalities of cancer cell lines were modeled against the BOLD-100 sensitivity profile, which revealed that genes related to ribosomal processes were associated with sensitivity to BOLD-100. Machine learning modeling of the sensitivity profile to BOLD-100 and gene expression data provided moderative predictive value. These findings provide further mechanistic understanding around BOLD-100 and support its development for additional cancer types. Full article

Most ECGs in European hospitals are recorded with equipment giving computer measured intervals and interpretation of the recording. In addition to measurements of interval and QRS axis, this interpretation frequently provides the Bazett’s-corrected QTc time. The introduction of computer-corrected QTc revealed QTc prolongation to be a frequent condition among medical patients. Nevertheless, the finding is frequently overlooked by the treating physician. The authors combine experience from a local hospital with a review of the current literature in this field in order to elucidate the importance of this risk factor both as congenital long QT syndrome and as acquired QT prolongation. Full article

Background: The relationship of Holter recordings of repolarization length to outcome in long QT syndrome (LQTS) is unknown. Methods: Holter recordings and initial 12 lead ECG QTc were related to outcome in 101 individuals with LQTS and 28 gene-negative relatives. Mean QTc (mQTc) and mean RTPc (R-wave to peak T-wave, mRTPc) using Bazett correction were measured, analyzing heart rates 40 to 120 bpm. Previously reported upper limit of normal (ULN) were: women and children (<15 years), mQTc 454, mRTPc 318 ms; men mQTc 446 ms, mRTPc 314 ms. Results: Measurements in LQTS patients were greatly prolonged; children and women mean mQTc 482 ms (range 406–558), mRTPc 351 ms (259–443); males > 15 years mQTc 469 ms (407–531), mRTPc 338 ms (288–388). Ten patients had cardiac arrest (CA), and 24 had arrhythmic syncope before or after the Holter. Holter values were more closely related to genotype status and symptoms than 12 lead QTc, e.g., sensitivity/specificity for genotype positive status, mRTPc > ULN (89%/86%); CA, mRTPc > 30 ms over ULN (48%/100%). Of 34 symptomatic (CA/syncope) patients, only 9 (26%) had 12 lead QTc > 500 ms, whereas 33/34 (94%) had an mRTPc or mQTc above ULN. In 10 with CA, all Holter measurements were > 15 ms above ULN, but only two had 12 lead QTc > 500 m. Conclusions: Holter average repolarization length, particularly mRTPc, reflects definite LQTS status and clinical risk better than the initial 12 lead QTc. Values below ULN indicate both a low risk of having LQTS and a low risk of cardiac events in the small percentage that do. Full article

Background: The effects of methadone-induced severe prolongation of the corrected QT interval (QTc) and sudden cardiac death appear unpredictable and sex-dependent. Genetic polymorphisms in the nitric oxide synthase 1 adaptor protein (NOS1AP) have been implicated in QTc prolongation in general populations. We investigated whether common NOS1AP variants interact with methadone in relation to QTc prolongation in patients with heroin dependence. Methods: We genotyped 17 NOS1AP variants spanning the entire gene in heroin-dependent patients who received a 12-lead electrocardiography (ECG) examination both at baseline and during maintenance methadone treatment in Cohort 1 and only during maintenance methadone treatment in Cohort 2. The QT interval was measured automatically by the Marquette 12SL program, and was corrected for heart rate using Bazett’s formula. Results: Cohort 1 consisted of 122 patients (age: 37.65 ± 8.05 years, 84% male, methadone dosage: 42.54 ± 22.17 mg/day), and Cohort 2 comprised of 319 patients (age: 36.9 ± 7.86 years, 82% male, methadone dosage: 26.08 ± 15.84 mg/day), with complete genotyping data for analyses. Before methadone, the QTc intervals increased with increasing age (r = 0.3541, p < 0.001); the age-adjusted QTc showed dose-dependent prolongation in men (r = 0.6320, p < 0.001), but abbreviation in women (r = −0.5348, p = 0.018) in Cohort 1. The pooled genotype-specific analysis of the two cohorts revealed that the QTc interval was significantly shorter in male carriers of the rs164148 AA variant than in male carriers of the reference GG genotype (GG: n = 262, QTc = 423 ± 1.4 ms; AA: n = 10, QTc = 404.1 ± 7 ms, p = 0.009), according to univariate analysis. The QTc remained shorter in male carriers of the rs164148 AA variant compared to GG genotype (423 ± 1.4 ms vs. 405.9 ± 6.9 ms, p = 0.016) in multivariate analysis after adjusting for age and methadone dosage. A cut-off QTc interval of <410 ms identifies 100% of AA carriers compared to none of GG carriers when receiving a daily methadone dosage of 30.6 ± 19.3 mg. There was no significant gene-drug interaction in contributing to the adjusted QTc (p = 0.2164) in male carriers of the rs164148 variants. Conclusions: Carriers of a common NOS1AP rs164148 AA genotype variant were associated with a shorter QTc interval in men receiving maintenance methadone treatment. This genetic polymorphism attenuates the QTc-prolonging effect by methadone, and thus may explain at least in part the unpredictable and heterogeneous risks for severe QTc prolongation and sudden cardiac death in patients on methadone. Full article

The use of zebrafish to explore cardiac physiology has been widely adopted within the scientific community. Whether this animal model can be used to determine drug cardiac toxicity via electrocardiogram (ECG) analysis is still an ongoing question. Several reports indicate that the recording configuration severely affects the ECG waveforms and its derived-parameters, emphasizing the need for improved characterization. To address this problem, we recorded ECGs from adult zebrafish hearts in three different configurations (unexposed heart, exposed heart, and extracted heart) to identify the most reliable method to explore ECG recordings at baseline and in response to commonly used clinical therapies. We found that the exposed heart configuration provided the most reliable and reproducible ECG recordings of waveforms and intervals. We were unable to determine T wave morphology in unexposed hearts. In extracted hearts, ECG intervals were lengthened and P waves were unstable. However, in the exposed heart configuration, we were able to reliably record ECGs and subsequently establish the QT-RR relationship (Holzgrefe correction) in response to changes in heart rate. Full article

Background: There are anecdotal reports on reversible QTc prolongation during therapeutic hypothermia (TH) for moderate to severe neonatal encephalopathy after asphyxia. As the QTc interval is a relevant biomarker for pharmacovigilance during medication development, a structured search and review on published neonatal QTc values to generate reference values is warranted to facilate medication development in this specific population. Methods: A structured search and literature assessment (PubMed, Embase, and Google Scholar) with ‘Newborn/Infant, QT and hypothermia’ was conducted (October 2021). Retrieved individual values were converted to QTc (Bazett) over postnatal age (day 1–7). Results: We retrieved 94 QTc intervals (during TH (n = 50, until day 3) or subsequent normothermia (n = 44, day 4–7)) in 33 neonates from 6 publications. The median (range) of QTc intervals during TH was 508 (430–678), and 410 (317–540) ms afterwards (difference 98 ms, or +28 ms/°C decrease). Four additional cohorts (without individual QTc intervals) confirmed the pattern and magnitude of the effect of body temperature on the QTc interval. Conclusions: We highlighted a relevant non-maturational covariate (°C dependent TH) and generated reference values for the QTc interval in this specific neonatal subpopulation. This knowledge on QTc during TH should be considered and integrated in neonatal medication development. Full article

Predicting fluid responsiveness in patients under mechanical ventilation with low tidal volume (VT) is challenging. This study evaluated the ability of carotid corrected flow time (FTc) assessed by ultrasound for predicting the fluid responsiveness during low VT ventilation. Patients under postoperative mechanical ventilation and clinically diagnosed with hypovolemia were enrolled. Carotid FTc and pulse pressure variation (PPV) were measured at VT of 6 and 10 mL/kg predicted body weight (PBW). FTc was calculated using both Bazett’s (FTcB) and Wodey’s (FTcW) formulas. Fluid responsiveness was defined as a ≥15% increase in the stroke volume index assessed by FloTrac/Vigileo monitor after administration of 8 mL/kg of balanced crystalloid. Among 36 patients, 16 (44.4%) were fluid responders. The areas under the receiver operating characteristic curves (AUROCs) for the FTcB at VT of 6 and 10 mL/kg PBW were 0.897 (95% confidence interval [95% CI]: 0.750–0.973) and 0.895 (95% CI: 0.748–0.972), respectively. The AUROCs for the FTcW at VT of 6 and 10 mL/kg PBW were 0.875 (95% CI: 0.722–0.961) and 0.891 (95% CI: 0.744–0.970), respectively. However, PPV at VT of 6 mL/kg PBW (AUROC: 0.714, 95% CI: 0.539–0.852) showed significantly lower accuracy than that of PPV at VT of 10 mL/kg PBW (AUROC: 0.867, 95% CI: 0.712–0.957; p = 0.034). Carotid FTc can predict fluid responsiveness better than PPV during low VT ventilation. However, further studies using automated continuous monitoring system are needed before its clinical use. Full article

Background: Parkinson’s disease (PD) is a possible risk factor for corrected QT interval (QTc) prolongation. PD patients frequently take QTc-prolonging drugs. The aim of the study was to assess the prevalence of QTc prolongation in PD and the influence of drugs and other potential risk factors on the QTc length in PD. Methods: 101 patients with PD and a good quality ECG were included in the study. The prolonged QTc was defined as ≥450 ms for men and ≥460 ms for women. Bazett’s (QTcB) and Framingham (QTcF) formulas were utilized to calculate QTc. Data about sex, age, PD duration, disease’s severity, comorbidities and QTc-prolonging drugs were collected. Multiple linear regressions with backward elimination were used to assess factors influencing the QTc. Results: A long QTc was presented in 13 patients (12.9%) for QTcB and 4 patients (4%) for QTcF. Longer QTc in PD patients was associated with older age, male sex and QTc-prolonging drugs regardless of the used formula. The QTcB was also significantly affected by the heart rate (HR). Conclusion: QTc prolongation is common in PD. Age, drugs and male gender are potential risk factors for QTc prolongation in PD. Full article

Previous experimental studies showed that increasing high-density lipoprotein cholesterol (HDL) cholesterol shortens cardiac ventricular repolarization and the QT interval corrected for heart rate (QTc). However, little is known about the epidemiological relationship between HDL and QTc. The potential antiarrhythmic effect of HDL cholesterol remains a speculative hypothesis. In this cross-sectional population based study in adults living in the Italian-speaking part of Switzerland, we aimed to explore the association between HDL cholesterol and the QTc interval in the general population. A total of 1202 subjects were screened. electrocardiogram (ECG) recordings, measurements of lipid parameters and other laboratory tests were performed. QTc was corrected using Bazett’s (QTc_Baz) and Framingham (QTc_Fram) formulas. HDL was categorized according to percentile distributions: <25th (HDL-1; ≤1.39 mmol/L); 25th–<50th (HDL-2; 1.40–1.69 mmol/L); 50th–<75th (HDL-3; 1.69–1.99 mmol/L); and ≥75th (HDL-4; ≥2.0 mmol/L). After exclusion procedures, data of 1085 subjects were analyzed. Compared with the HDL reference group (HDL-1), HDL-2 and HDL-3 were associated with a reduction of QTc_Baz and QTc_Fram duration in crude (HDL-2, QTc_Baz/QTc_Fram: β-11.306/–10.186, SE 4.625/4.016; p = 0.016/0.012; HDL-3, β-12.347/–12.048, SE 4.875/4.233, p = 0.012/<0.001) and adjusted (HDL-2: β-11.697/–10.908, SE 4.333/4.151, p < 0.001/0.010; HDL-3 β-11.786/–11.002, SE 4.719/4.521, p = 0.014/0.016) linear regression models in women. In adjusted logistic regression models higher HDL, were also associated with lower risk of prolonged QTc_Baz/QTc_Fram (HDL-2: OR 0.16/0.17, CI 0.03–0.83/0.47–0.65; HDL-3: OR 0.10/0.14, CI 0.10–0.64/0.03–0.63) in women. Restricted cubic spline analysis confirmed a non linear association (p < 0.001). The present findings indicate an epidemiological association between HDL cholesterol and QTc duration. To draw firm conclusions, further investigations in other populations and with a prospective cohort design are needed. Full article