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Objective: The association between common electrocardiogram (ECG) markers and Alzheimer's disease has been scarcely investigated, and it is unknown if ECG markers can improve risk prediction. Thus, we aimed to examine the association between common ECG markers and Alzheimer's disease in a large population. Methods: We studied the association between ECG markers and Alzheimer's disease using Cox models with adjustment for age, sex, and comorbidities using a large primary care population of patients aged 60 years or more. Results: We followed 172,236 subjects for a median of 7.5 years. Increased PR interval (hazard ratio for PR > 188 ms: 0.76 [95% confidence interval: 0.69–0.83, p < 0.001) and increased QTc interval (hazard ratio for QTc = [426;439]: 0.90 [0.83–0.98], p = 0.02) were associated with a decreased rate of Alzheimer's disease. A positive Sokolow-Lyon index >35 mm (1.22 [1.13–1.33], p < 0.001) and increased T-wave amplitude >4.1 mm (1.15 [1.04–1.27]) were associated with an increased rate of Alzheimer's disease. Upon addition of ECG markers to a reference model, 10-year prediction area under the receiver-operator characteristics curve (AUC) improved by 0.39 [0.06–0.67] %-points. The 10-year absolute risk of Alzheimer's disease was 6.5% and 5.2% for an 82-year old female and a male, respectively, with a favorable ECG, and 12% and 9.2%, respectively, with an unfavorable ECG, almost twice as high. Conclusions: We identified several common ECG markers which were associated with Alzheimer's disease, and which improved risk prediction for Alzheimer's disease.

Objectives We evaluated the long-term stability of thyroid peroxidase antibody (anti-TPO). Methods In the Danish General Suburban Population Study (GESUS), serum samples were biobanked at −80 °C during 2010–2013. In a paired design with 70 subjects, we compared anti-TPO (30–198 U/mL) measured on fresh serum on Kryptor Classic in 2010–2011 (anti-TPOfresh) with anti-TPO remeasured on frozen serum (anti-TPOfrozen) on Kryptor Compact Plus in 2022. Both instruments used the same reagents and the anti-TPOn automated immunofluorescent assay, which was calibrated against the international standard NIBSC 66/387, based on the Time Resolved Amplified Cryptate Emission (TRACE) technology from BRAHMS. Values greater than 60 U/mL are regarded as positive in Denmark with this assay. Statistical comparisons included Bland-Altman, Passing-Bablok regression, and Kappa statistic. Results The mean follow-up time was 11.9 years (SD: 0.43). For anti-TPOfrozen vs. anti-TPOfresh, the line of equality was within the confidence interval of the absolute mean difference [5.71 (−0.32; 11.7) U/mL] and the average percentage deviation [+2.22% (−3.89%; +8.34%)]. The average percentage deviation of 2.22% did not exceed analytical variability. Passing-Bablok regression revealed both a statistically significant systematic and proportional difference: Anti-TPOfrozen=−22.6 + 1.22*(anti-TPOfresh). Frozen samples were correctly classified as positive in 64/70 (91.4%; Kappa=71.8%). Conclusions Anti-TPO serum samples in the range 30–198 U/mL were stable after 12-years of storage at −80 °C with an estimated nonsignificant average percentage deviation of +2.22%. This comparison is based on Kryptor Classic and Kryptor Compact Plus, which used identical assays, reagents, and calibrator, but for which the agreement in the range 30–198 U/mL is unclarified.

Aim β-blockers are the first line of treatment in patients with congenital long QT syndrome (cLQTS) (class I or II recommendation) in order to prevent malignant arrhythmias. Hence, we examined long-term β-blocker adherence and associated risk factors among patients with cLQTS. Methods and results Danish patients with cLQTS claiming a prescription for any β-blocker after their cLQTS diagnosis were identified using data from nationwide registries and specialized inherited cardiac disease clinics (1995–2017). Patients were followed for up to 5 years. Treatment breaks >60 days were assessed (i.e. proxy for reduced adherence). Multivariable Cox regression was used to identify risk factors associated with breaks of >60 days in β-blocker treatment. Overall, 500 out of 633 (79%) patients with cLQTS claimed at least one prescription for any β-blocker after cLQTS diagnosis. During follow-up, 38.4% had a treatment break. Risk factors significantly associated with treatment breaks were implantable cardioverter defibrillator (ICD) [hazard ratio (HR) = 1.65, 95% confidence interval (CI): 1.08–2.53], β-blocker side effects (HR = 2.69, 95% CI: 1.75–4.13), and psychiatric disease (HR = 1.63, 95% CI: 1.04–2.57). In contrast, patients presenting with ventricular tachycardia/syncope as cLQTS disease manifestation were less likely to have a treatment break compared with asymptomatic patients (HR = 0.55, 95% CI: 0.33–0.92). Conclusion Reduced β-blocker adherence was common with more than a third of patients having a treatment break >60 days after cLQTS diagnosis. Patients with psychiatric disease, self-reported β-blocker side effects, and an ICD were more likely to display reduced adherence, whereas a severe cLQTS disease manifestation was associated with optimal β-blocker adherence.

AIMS: The voltage-gated potassium channel K v 11.1 is important for repolarising the membrane potential in excitable cells such as myocytes, pancreatic α- and β-cells. Moxifloxacin blocks the K v 11.1 channel and increases the risk of hypoglycaemia in patients with diabetes. We investigated glucose regulation and secretion of glucoregulatory hormones in young people with and without moxifloxacin a drug known to block the K v 11.1 channel. MATERIAL AND METHODS: The effect of moxifloxacin (800 mg/day for four days) or placebo on glucose regulation was assessed in a randomised, double-blind, crossover study of young men and women (age 20-40 years and BMI 18.5-27.5 kg/m 2 ) without chronic disease, using 6-hour oral glucose tolerance tests (OGTT) and continuous glucose monitoring (CGM). RESULTS: Thirty-eight participants completed the study. Moxifloxacin prolonged the QTcF-interval and increased heart rate. Hypoglycaemia was more frequently observed with moxifloxacin, both during the eight days of CGM and during the OGTT. Hypoglycaemia questionnaire scores were higher after intake of moxifloxacin. Moxifloxacin reduced early plasma-glucose response (AUC 0-30min ) by 7% (95%CI: -9% to -4%, pCONCLUSIONS: In young men and women, moxifloxacin a drug known to block the K v 11.1 channel increased QT interval, decreased glucose levels, and was associated with increased muscle insulin sensitivity and more frequent episodes of hypoglycaemia. This article is protected by copyright. All rights reserved.

Aims Although mobile health tools using photoplethysmography (PPG) technology have been validated for the detection of atrial fibrillation (AF), their utility for heart rate assessment during AF remains unclear. Therefore, we aimed to evaluate the accuracy of continuous PPG-based 1 min mean heart rate assessment during AF. Methods and results Persistent AF patients were provided with Holter electrocardiography (ECG) (for ≥24 h) simultaneously with a PPG-equipped smartwatch. Both the PPG-based smartwatch and Holter ECG automatically and continuously monitored patients’ heart rate/rhythm. ECG and PPG recordings were synchronized and divided into 1 min segments, from which a PPG-based and an ECG-based average heart rate estimation were extracted. In total, 47 661 simultaneous ECG and PPG 1 min heart rate segments were analysed in 50 patients (34% women, age 73 ± 8 years). The agreement between ECG-determined and PPG-determined 1 min mean heart rate was high [root mean squared error (RMSE): 4.7 bpm]. The 1 min mean heart rate estimated using PPG was accurate within ±10% in 93.7% of the corresponding ECG-derived 1 min mean heart rate segments. PPG-based 1 min mean heart rate estimation was more often accurate during night-time (97%) than day-time (91%, P < 0.001) and during low levels (96%) compared to high levels of motion (92%, P < 0.001). A neural network with a 10 min history of the recording did not further improve the PPG-based 1 min mean heart rate assessment [RMSE: 4.4 (95% confidence interval: 3.5–5.2 bpm)]. Only chronic heart failure was associated with a lower agreement between ECG-derived and PPG-derived 1 min mean heart rates (P = 0.040). Conclusion During persistent AF, continuous PPG-based 1 min mean heart rate assessment is feasible in 60% of the analysed period and shows high accuracy compared with Holter ECG for heart rates

ObjectiveTo examine workforce attachment among patients with congenital long QT syndrome (cLQTS) following diagnosis and identify factors associated with workforce attachment.Methods and resultsIn this nationwide cohort study, all patients diagnosed with cLQTS in Denmark between 1996 and 2016 aged 18–60 years at diagnosis were identified using nationwide registries. Patients attached to the workforce at diagnosis were included. Attachment to the workforce 1 year after cLQTS diagnosis was examined and compared with a background population matched 1:4 on age, sex and employment status. Multiple logistic regression was performed to identify factors associated with 1-year workforce detachment among patients with cLQTS. 298 patients fulfilled the inclusion criteria. Six months after cLQTS diagnosis, 90.9% of patients with cLQTS were attached to the workforce compared with 95.0% in the background population (p=0.006 for difference). One year after diagnosis, 93.3% of patients with cLQTS were attached to the workforce compared with 93.8% in the background population (p=0.26). Among patients with cLQTS, a severe cLQTS disease manifestation was associated with workforce detachment 1 year after diagnosis (compared with asymptomatic patients; aborted cardiac arrest OR 20.4 (95% CI, 1.7 to 249.9); ventricular tachycardia/syncope OR 10.9 (95% CI, 1.1 to 110.5)). No other associated factors were identified.ConclusionsMore than 90% of patients with cLQTS remained attached to the workforce 1 year after diagnosis, which was similar to a matched background population. Patients with a severe cLQTS disease manifestation were less likely to be attached to the workforce 1 year after diagnosis.

BackgroundElectrocardiographic T-wave morphology is used in drug safety studies as an adjunct to the QT c interval, but few measurements of T-wave morphology can be interpreted in clinical practice. Morphology combination score (MCS) is a combination of T-wave flatness/peakedness, asymmetry, and notching, enabling easy visual assessment of T-wave morphology. We aimed to test the association between T-wave morphology, quantified by MCS, and mortality.MethodsWe included electrocardiograms recorded in 2001–2011 from 342,294 primary care patients. Using Cox regression, we evaluated the association between MCS, cardiovascular death, and all-cause mortality, adjusting for heart rate, QT c, QT-prolonging drugs, diabetes, ischemic heart disease, hypertension, and congestive heart failure.Results270,039 individuals (44% men, median age 55 [inter-quartile range: 42–67 years]) were included and followed for a median of 9.3 years, during which time 13,489 (5.0%) died from cardiovascular causes and 50,481 (18.7%) from any cause. High values of MCS (i.e. asymmetric, flattened, and/or notched T waves) were associated with an adjusted mortality Hazard Ratio of 1.75 (95% CI 1.62–1.89) and 1.61 (1.43–1.92) for women and men, respectively. Low values of MCS (i.e. peaked and symmetric T waves) were associated with a Hazard Ratio of 1.18 (1.08–1.28) and 1.71 (1.48–1.98) for women and men, respectively.ConclusionsIn a large primary care population, we found that T-wave asymmetry, flatness, and notching provided prognostic information on mortality independent of heart rate, QTc, and baseline comorbidities.

Introduction Hydroxychloroquine has been suggested as possible treatment for Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2). Studies reported an increased risk of QTcF-prolongation after treatment with hydroxychloroquine. The aim of this study was to analyze the concentration-dependent effects of hydroxychloroquine on the ventricular repolarization, including QTcF-duration and T-wave morphology. Methods Twenty young (≤30 years) and twenty elderly (65 - 75 years) healthy male subjects were included. Subjects were randomized to receive either a total dose of 2400 mg hydroxychloroquine over 5 days, or placebo (ratio 1:1). Follow-up duration was 28 days. ECGs were recorded as triplicate at baseline and four post-dose single recordings, followed by hydroxychloroquine concentration measurements. ECG intervals (RR, QRS, PR, QTcF, J-Tpc, Tp-Te) and T-wave morphology, measured with the Morphology Combination Score (MCS), were analyzed with a pre-specified linear mixed effects concentration-effect model. Results There were no significant associations between hydroxychloroquine concentrations and ECG characteristics, including RR-, QRS- and QTcF-interval (p = 0.09, 0.34, 0.25). Mean ΔΔQTcF-interval prolongation did not exceed 5 ms and the upper limit of the 90% confidence interval did not exceed 10 ms at the highest measured concentrations (200ng/mL). There were no associations between hydroxychloroquine concentration and the T-wave morphology (p = 0.34 for MCS). There was no significant effect of age group on ECG characteristics. Conclusion In this study, hydroxychloroquine did not affect ventricular repolarization, including the QTcF-interval and T-wave morphology, at plasma concentrations up to 200 ng/mL. Based on this analysis, hydroxychloroquine does not appear to increase the risk of QTcF-induced arrhythmias.

Purpose: The cardiac T-wave peak-to-end interval (Tpe) is thought to reflect dispersion in ventricular repolarisation, with abnormalities in Tpe associated with increased risk of arrhythmia. Extracellular K+ modulates cardiac repolarisation, and since arterial plasma K+ concentration ([K+]) rapidly increases during and declines following exercise, we investigated the relationship between [K+] and Tpe with exercise. Methods: Serial ECGs (Tpe, Tpe/QT ratio) and [K+] were obtained from 8 healthy, normokalaemic volunteers and 22 patients with end-stage renal disease (ESRD), at rest, during, and after exhaustive exercise. Results: Post-exercise [K+] nadir was 3.1 ± 0.1, 5.0 ± 0.2 and 4.0 ± 0.1 mmol.L−1 (mean ± SEM) for healthy participants and ESRD patients before and after haemodialysis, respectively. In healthy participants, compared to pre-exercise, recovery-induced low [K+] was associated with a prolongation of Tpe (110 ± 8 vs. 87 ± 5 ms, respectively, p = 0.03) and an increase in Tpe/QT ratio (0.28 ± 0.01 vs. 0.23 ± 0.01, respectively, p = 0.01). Analyses of serial data revealed [K+] as a predictor of Tpe in healthy participants (β = -0.54 ±0.05, p < 0.0001), in ESRD patients (β = -0.75 ± 0.06, p < 0.0001) and for all data pooled (β = -0.61 ± 0.04, p < 0.0001). The [K+] was also a predictor of Tpe/QT ratio in healthy participants and ESRD patients. Conclusions: Tpe and Tpe/QT ratio are predicted by [K+] during exercise. Low [K+] during recovery from exercise was associated with increased Tpe and Tpe/QT, indicating accentuated dispersion of ventricular repolarisation. The findings suggest that variations in [K+] with physical exertion may unmask electrophysiological vulnerabilities to arrhythmia.

Aims To determine the risk of major adverse cardiovascular events (MACE) and death, associated with an early large and rapid decline in glycated haemoglobin (HbA1C) following first time initiation of an oral antidiabetic drug (OAD). Methods and results We included 10 518 primary care patients with type 2 diabetes, who initiated an OAD for the first time. For each individual, we measured a decline in HbA1C, as the difference between the pre-treatment HbA1C (within 3 months before OAD initiation) and the post-treatment HbA1C (within 1.5–4.5 months after OAD initiation), divided by the time between the two measurements. The decline was reported in mmol/mol change per 3 months in HbA1C and categorized by the median decline into levels of steep [≥9 mmol/mol (≥0.8%)] and flat decline [62 mmol/mol). Multiple Cox regression was used to study the effect of decline (steep vs. flat) on the outcome hazard rates separately for patients with low and high pre-treatment HbA1C. Analyses were adjusted for age, sex, traditional cardiovascular risk factors, severe comorbidities, and concomitant medication treatment. During a median follow-up time of 7.7 years, 1625 developed MACE and 2323 died. We found that a steep decline vs. a flat decline was significantly associated with a decreased hazard for MACE, both in individuals with high [hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.69–0.94; P = 0.005] and low pre-treatment HbA1C (HR 0.79; 95% CI 0.66–0.96; P = 0.015). The hazard of MACE was more pronounced on the short-term vs. long-term in individuals with high pre-treatment HbA1C. We found no significant association between combinations of pre-treatment HbA1C and decline categories and hazard of all-cause mortality. However, a combination of a low pre-treatment HbA1C and steep decline was associated with increased 1-year mortality (HR 1.52; 95% CI 1.00–2.29; P = 0.048) and hypoglycaemia (HR 1.82; 95% CI 1.11–2.98; P = 0.017). Conclusion A combination of a high pre-treatment HbA1C and a steep decline in HbA1C was associated with a decreased short-term risk of MACE. A low pre-treatment HbA1C and a steep decline was associated with a long-term reduced risk of MACE, but a short-term increased risk of death and hypoglycaemia.

Mitochondrial DNA (mtDNA) haplogroup (hg) H has been reported as a susceptibility factor for hypertrophic cardiomyopathy (HCM). This was established in genetic association studies, however, the SNP or SNP’s that are associated with the increased risk have not been identified. Hg H is the most frequent European mtDNA hg with greater than 80 subhaplogroups (subhgs) each defined by specific SNPs. We tested the hypothesis that the distribution of H subhgs might differ between HCM patients and controls. The subhg H distribution in 55 HCM index cases was compared to that of two Danish mtDNA hg H control groups (n = 170 and n = 908, respectively). In the HCM group, H and 12 different H subhgs were found. All these, except subhgs H73, were also found in both control groups. The HCM group was also characterized by a higher proportion of H3 compared to H2. In the HCM group the H3/H2 proportion was 1.7, whereas it was 0.45 and 0.54 in the control groups. This tendency was replicated in an independent group of Hg H HCM index cases (n = 39) from Queensland, Australia, where the H3/H2 ratio was 1.5. In conclusion, the H subhgs distribution differs between HCM cases and controls, but the difference is subtle, and the understanding of the pathogenic significance is hampered by the lack of functional studies on the subhgs of H.

Background: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD. Methods: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies. Results: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci ( TTN , CAND2 , SCN10A , PITX2 , CAV1 , SYNPO2L , SOX5 , TBX5, MYH6, RPL3L ). The top variants at known sarcomere genes ( TTN, MYH6 ) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A ) were associated with longer PWD but lower AF risk. Conclusions: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.

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 additive, not exponential. Hyperglycaemia was associated with a significantly greater mean QTc-prolonging effect in females, but the mean peak increase with the addition of moxifloxacin was the same for males and females. This apparent sex difference was likely due to the exclusive use of basal insulin in the male patients, which provided a low level of exogenous insulin during the study assessments thereby mitigating the effects of hyperglycaemia on QTc. This effect was partially overcome by Moxifloxacin administration, suggesting both hyperglycaemia and moxifloxacin prolong QTc by different mechanisms, based on subinterval analysis. Conclusions Hyperglycaemia was found to be a significant cause of QTc prolongation and the additional effect of a QTc-prolonging positive control (moxifloxacin) was found to be additive. Given the high risk of sudden cardiac death in type 1 diabetes mellitus, extra caution should be exercised when prescribing any medication in this cohort for QTc effects, and further research needs to be undertaken to elucidate the exact mechanism underlying this finding and explore the potential prescribing risk in diabetes. Trial Registration NCT number: NCT01984827. Graphical abstract

OBJECTIVES: To determine whether electrocardiogram (ECG) markers are associated with incident non-Alzheimer's dementia (non-AD) and whether these markers also improve risk prediction for non-AD.MATERIALS AND METHODS: We retrospectively included 170,605 primary care patients aged 60 years or older referred for an ECG by their general practitioner and followed them for a median of 7.6 years. Using Cox regression, we reported hazard ratios (HRs) for electrocardiogram markers. Subsequently, we evaluated if addition of these electrocardiogram markers to a clinical model improved risk prediction for non-AD using change in area under the receiver-operator characteristics curve (AUC).RESULTS: The 5-year cumulative incidence of non-AD was 3.4 %. Increased heart rate (HR=1.06 pr. 10 bpm [95% confidence interval: 1.04-1.08], p 35 mm (HR=1.31 [1.18-1.46], pCONCLUSIONS: ECG markers typical of an elevated cardiovascular risk profile were associated with non-AD and improved both 5-year and 10-year risk predictions for non-AD.

Voltage-gated potassium (K

OBJECTIVE LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown. RESEARCH DESIGN AND METHODS We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses. RESULTS A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (β = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04). CONCLUSIONS These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.

Recent global developments underscore the prominent role big data have in modern medical science. But privacy issues constitute a prevalent problem for collecting and sharing data between researchers. However, synthetic data generated to represent real data carrying similar information and distribution may alleviate the privacy issue. In this study, we present generative adversarial networks (GANs) capable of generating realistic synthetic DeepFake 10-s 12-lead electrocardiograms (ECGs). We have developed and compared two methods, named WaveGAN* and Pulse2Pulse. We trained the GANs with 7,233 real normal ECGs to produce 121,977 DeepFake normal ECGs. By verifying the ECGs using a commercial ECG interpretation program (MUSE 12SL, GE Healthcare), we demonstrate that the Pulse2Pulse GAN was superior to the WaveGAN* to produce realistic ECGs. ECG intervals and amplitudes were similar between the DeepFake and real ECGs. Although these synthetic ECGs mimic the dataset used for creation, the ECGs are not linked to any individuals and may thus be used freely. The synthetic dataset will be available as open access for researchers at OSF.io and the DeepFake generator available at the Python Package Index (PyPI) for generating synthetic ECGs. In conclusion, we were able to generate realistic synthetic ECGs using generative adversarial neural networks on normal ECGs from two population studies, thereby addressing the relevant privacy issues in medical datasets.

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 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 identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

BackgroundIn long QT syndrome (LQTS), beta blockers prevent arrhythmias. As a supplement, means to increase potassium has been suggested. We set to investigate the effect of moderate potassium elevation on cardiac repolarisation.MethodsPatients with LQTS with a disease-causing KCNQ1 or KCNH2 variant were included. In addition to usual beta-blocker treatment, patients were prescribed (1) 50 mg spironolactone (low dose) or (2) 100 mg spironolactone and 3 g potassium chloride per day (high dose+). Electrocardiographic measures were obtained at baseline and after 7 days of treatment.ResultsTwenty patients were enrolled (10 low dose and 10 high dose+). One patient was excluded due to severe influenza-like symptoms, and 5 of 19 patients completing the study had mild side effects. Plasma potassium in low dose did not increase in response to treatment (4.26±0.22 to 4.05±0.19 mmol/L, p=0.07). Also, no change was observed in resting QTcF (QT interval corrected using Fridericia's formula) before versus after treatment (478±7 vs 479±7 ms, p=0.9). In high dose+, potassium increased significantly from 4.08±0.29 to 4.48±0.54 mmol/L (p=0.001). However, no difference in QTcF was observed comparing before (472±8 ms) versus after (469±8 ms) (p=0.66) high dose+ treatment. No patients developed hyperkalaemia.ConclusionIn patients with LQTS, high dose+ treatment increased plasma potassium by 0.4 mmol/L without cases of hyperkalaemia. However, the potassium increase did not shorten the QT interval and several patients had side effects. Considering the QT interval as a proxy for arrhythmic risk, our data do not support that potassium-elevating treatment has a role as antiarrhythmic prophylaxis in patients with LQTS with normal-range potassium levels.Trial registration numberNCT03291145.