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The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease. The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

Background: Subjects receiving levothyroxine (LT4) treatment have increased prevalence of depression, anxiety, and antidepressant use, but whether the underlying mechanism relates to thyroid autoimmunity is still unclarified.Methods: This is a population-based longitudinal study. Baseline biochemical and questionnaire data from the Danish General Suburban Population Study (GESUS) in 2010-2013 were linked with individual-level longitudinal data in national health registries. The aim was to investigate the associations between thyroid peroxidase antibodies (TPOAbs) and LT4 treatment, separately and through interaction, and at least one redeemed prescription for antidepressants. Logistic and Cox regression were used to evaluate initiation of antidepressant use before and after the baseline examination in GESUS, respectively. All exposures and covariates were fixed at the date of baseline examination. Thyroid autoimmunity was defined as serum TPOAbs >60 U/mL. Adjustments included sex, age, education, income, Charlson comorbidity index, smoking, and alcohol. Sensitivity analyses were performed for missing variables, exclusion of lithium use, exclusion of thyroid surgery, and conservative definitions for LT4 treatment and antidepressant use requiring at least two prescriptions.Results: We included 12,894 individuals, of whom 2353 (18%) had "past or current" antidepressant use at baseline, leaving 10,541 individuals at risk for incident antidepressant use after baseline. The median follow-up was 7.8 years during which 783 individuals (7.4% of 10,541 individuals) had incident antidepressant use. TPOAb positivity was not associated with "past or current" (odds ratio [OR] 0.90 [confidence interval, CI 0.78-1.03], p = 0.13) nor incident antidepressant use (hazard ratio [HR] 1.02 [CI 0.83-1.25], p = 0.88). LT4 treatment was associated with increased "past or current" antidepressant use (OR 1.33 [CI 1.10-1.62], p = 0.004) and increased incident antidepressant use (HR 1.38

Background Patients with Type 1 diabetes mellitus have been shown to be at a two to ten-fold higher risk of sudden cardiac death (SCD) (Svane et al., Curr Cardiol 2020; 22:112) than the general population, but the underlying mechanism is unclear. Hyperglycaemia is a recognised cause of QTc prolongation; a state patients with type 1 diabetes are more prone to, potentially increasing their risk of ventricular arrhythmia. Understanding the QTc prolongation effect of both hyperglycaemia and the concomitant additive risk of commonly prescribed QTc-prolonging drugs such as Moxifloxacin may help to elucidate the mechanism of sudden cardiac death in this cohort. This single-blinded, placebo-controlled study investigated the extent to which hyperglycaemia prolongs the QTc in controlled conditions, and the potential additive risk of QTc-prolonging medications.Methods 21 patients with type 1 diabetes mellitus were enrolled to a placebo-controlled crossover study at a single clinical trials unit. Patients underwent thorough QTc assessment throughout the study. A 'hyperglycaemic clamp' of oral and intravenous glucose was administered with a target blood glucose of > 25 mM and maintained for 2 h on day 1 and day 3, alongside placebo on day 1 and moxifloxacin on day 3. Day 2 served as a control day between the two active treatment days. Thorough QTc assessment was conducted at matched time points over 3 days, and regular blood sampling was undertaken at matched time intervals for glucose levels and moxifloxacin exposure.Results Concentration-effect modelling showed that acute hyperglycaemia prolonged the QTc interval in female and male volunteers with type 1 diabetes by a peak mean increase of 13 ms at 2 h. Peak mean QTc intervals after the administration of intravenous Moxifloxacin during the hyperglycaemic state were increased by a further 9 ms at 2 h, to 22 ms across the entire study population. Regression analysis suggested this additional increase was addi

Voltage-gated potassium (K-v) channels play an important role in the repolarization of a variety of excitable tissues, including in the cardiomyocyte and the pancreatic beta cell. Recently, individuals carrying loss-of-function (LoF) mutations in KCNQ1, encoding K(v)7.1, and KCNH2 (hERG), encoding K(v)11.1, were found to exhibit post-prandial hyperinsulinaemia and episodes of hypoglycaemia. These LoF mutations also cause the cardiac disorder long QT syndrome (LQTS), which can be aggravated by hypoglycaemia. Interestingly, patients with LQTS also have a higher burden of diabetes compared to the background population, an apparent paradox in relation to the hyperinsulinaemic phenotype, and KCNQ1 has been identified as a type 2 diabetes risk gene. This review article summarizes the involvement of delayed rectifier K+ channels in pancreatic beta cell function, with emphasis on K(v)7.1 and K(v)11.1, using the cardiomyocyte for context. The functional and clinical consequences of LoF mutations and polymorphisms in these channels on blood glucose homeostasis are explored using evidence from pre-clinical, clinical and genome-wide association studies, thereby evaluating the link between LQTS, hyperinsulinaemia and type 2 diabetes.

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 10(-13)). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.

Limited access to medical data is a barrier on developing new and efficient machine learning solutions in medicine such as computer-aided diagnosis, risk assessments, predicting optimal treatments and home-based personal healthcare systems. This paper presents DeepSynthBody: a novel framework that overcomes some of the inherent restrictions and limitations of medical data by using deep generative adversarial networks to produce synthetic data with characteristics similar to the real data, so-called DeepSynth (deep synthetic) data. We show that DeepSynthBody can address two key issues commonly associated with medical data, namely privacy concerns (as a result of data protection rules and regulations) and the high costs of annotations. To demonstrate the full pipeline of applying DeepSynthBody concepts and user-friendly functionalities, we also describe a synthetic medical dataset generated and published using our framework. DeepSynthBody opens a new era of machine learning applications in medicine with a synthetic model of the human body.

Cortexolone 17 alpha-propionate, also known as clascoterone, is a potent androgen receptor inhibitor intended for the topical treatment of skin diseases associated with androgenic pathway alterations. In nonclinical studies, cortexolone 17 alpha-propionate was found to have a weak inhibitory effect on human Ether-a-go-go-Related Gene (hERG) potassium channels, which are vital for normal electrical activity in the heart. When used in a cream formulation, little cortexolone 17 alpha-propionate is absorbed. However, the solution formulation developed for the treatment of androgenetic alopecia leads to a measurable systemic concentration and accumulation of the antiandrogen. This phase 1 study assessed the effect of cortexolone 17 alpha-propionate on the QTc interval using concentration-effect analysis and the effect of a meal on QTc to confirm assay sensitivity. Thirty-two volunteers were randomly assigned to receive the active drug or a matching vehicle as placebo. Participants were dosed twice daily on days 1 to 3 (225 mg applied topically as a 7.5% solution 12 hours apart) and once on day 4. Pharmacokinetic and electrocardiogram assessments were performed after supratherapeutic doses. Assay sensitivity was successfully confirmed by using the food effect on the QTc interval. The results of this concentration-QTc analysis demonstrate that cortexolone 17 alpha-propionate and its metabolite/degradation product had no effect on the QTc interval in the concentration range tested.

Introduction Hydroxychloroquine (HCQ) has been proposed as a SARS-CoV-2 treatment but the frequency of long QT (LQT) during use is unknown.Objective To conduct a meta-analysis of the frequency of LQT in patients with SARS-CoV-2 infection treated with HCQ.Data Sources PubMed, EMBASE, Google Scholar, the Cochrane Database of Systematic Reviews and preprint servers (medRxiv, Research Square) were searched for studies published between December 2019 and June 30, 2020.Methods Effect statistics were pooled using random effects. The quality of observational studies and randomized controlled trials was appraised with STROBE and the Cochrane Risk of Bias Assessment tools, respectively.Outcomes Critical LQT was defined as: (1) maximum QT corrected (QTc) >= 500 ms (if QRS = 550 ms (if QRS >= 120 ms), and (2) QTc increase >= 60 ms.Results In the 28 studies included (n = 9124), the frequency of LQT during HCQ treatment was 6.7% (95% confidence interval [CI]: 3.7-10.2). In 20 studies (n = 7825), patients were also taking other QT-prolonging drugs. The frequency of LQT in the other 8 studies (n = 1299) was 1.7% (95% CI: 0.3-3.9). Twenty studies (n = 6869) reported HCQ discontinuation due to LQT, with a frequency of 3.7% (95% CI: 1.5-6.6). The frequency of ventricular arrhythmias during HCQ treatment was 1.68% (127/7539) and that of arrhythmogenic death was 0.69% (39/5648). Torsades de Pointes occurred in 0.06% (3/5066). Patients aged 60 years were at highest risk of HCQ-associated LQT (P <0.001).Conclusions HCQ-associated cardiotoxicity in SARS-CoV-2 patients is uncommon but requires ECG monitoring, particularly in those aged > 60 years and/or taking other QT-prolonging drugs. (C) 2020 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.

Aims: Potassium disturbances are common and associated with increased morbidity and mortality, even in patients without prior cardiovascular disease. We examined six electrocardiographic (ECG) measures and their association to serum potassium levels. Methods and results: From the Copenhagen General Practitioners' Laboratory, we identified 163,547 individuals aged >= 16 years with a first available ECG and a concomitant serum potassium measurement during 2001-2011. Restricted cubic splines curves showed a non-linear relationship between potassium and the Fridericia corrected QT (QTcF) interval, T-wave amplitude, morphology combination score (MCS), PR interval, P-wave amplitude and duration. Therefore, potassium was stratified in two intervals K: 2.0-4.1 mmol/L and 4.2-6.0 mmol/L for further analyses. Within the low potassium range, we observed: QTcF was 12.8 ms longer for each mmol/L decrease in potassium (p < 0.0001); T-wave amplitude was 43.1 mu V lower for each mmol/L decrease in potassium (p < 0.0001); and MCS was 0.13 higher per mmol/L decrease in potassium (p < 0.001). Moreover, P-wave duration and PR interval were prolonged by 2.7 and 4.6 ms for each mmol/L decrease in potassium (p < 0.0001), respectively. Within the lowest potassium range (2.0-4.1 mmol/L) P-wave amplitude was 3.5 mu V higher for each mmol/L decrease in potassium (p < 0.0001). Within the high potassium range associations with the above-mentioned ECG parameters were much weaker. (C) 2018 Elsevier Inc. All rights reserved.

BACKGROUND: In long QT syndrome type 1 (LQT1), the location and type of mutations have been shown to affect the clinical outcome. Although haploinsufficiency, including stop-codon and frameshift mutations, has been associated with a lower risk of cardiac events in patients with LQT1, nonsense mutations have been presumed functionally equivalent.OBJECTIVE: The purpose of this study was to evaluate clinical differences between patients with nonsense mutations.METHODS: The study sample comprised 1090 patients with genetically confirmed mutations. Patients were categorized into 5 groups, depending on mutation type and location: missense not located in the high-risk cytoplasmic loop (c-loop) (n = 698), which is used as reference; missense c-loop (n = 192); stop-codon (n = 67); frameshift (n = 39); and others (n = 94). The primary outcome was a composite end point of syncope, aborted cardiac arrest, and long QT syndrome-related death (cardiac events). Outcomes were evaluated using the multivariate Cox proportional hazards regression analysis. Standard patch clamp techniques were used.RESULTS: Compared to patients with missense non-c-loop mutations, the risk of cardiac events was reduced significantly in patients with stop-codon mutations (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.34-0.96; P = .035), but not in patients with frameshift mutations (HR 1.01; 95% CI 0.58-1.77; P = .97). Our data suggest that currents of the most common stop-codon mutant channel (Q530X) were larger than those of haploinsufficient channels (wild type: 42 ± 6 pA/pF, n = 20; Q530X+wild type: 79 ± 14 pA/pF, n = 20; P < .05) and voltage dependence of activation was altered.CONCLUSION: Stop-codon mutations are associated with a lower risk of cardiac events in patients with LQT1, while frameshift mutations are associated with the same risk as the majority of the missense mutations. Our data indicate functional differences between these previously consider

The fertilized chicken egg (embryonic chicken) shares the basic mechanism of electrophysiology and ionic currents with mammalian hearts. However, little is known about the cardiac repolarization process during embryo growth. We examined if the electrocardiographic QT interval was dependent on the stage of embryonic development. ECGs were recorded from 4 fertilized chicken eggs for 6 days (day 13 to day 18). Eggs were kept in an incubator with a temperature of 37.4°C. Chronic electrodes were implanted and a 5-minute ECG was recorded each day. Three measurements were made in noise free segments: Heart rate, QT interval, and the Fridericia corrected QT interval (QTcF), and an average value was calculated. The QTcF interval decreased during embryo development. On day 18, QTcF was shorter than QTcF on day 13: 341 ms (95% CI: 332 ms to 349 ms) versus 417 (95% CI: 325 ms to 509 ms), p=0.037. In fertilized chicken eggs, the repolarization process changes during development. This property makes the chicken embryo an interesting model for the study of drug effects on the QT interval at different stages of embryo development.