Publications by authors named "Jørgen K Kanters"

117 Publications

Plasma potassium concentration and cardiac repolarisation markers, T-T and T-T/QT, during and after exercise in healthy participants and in end-stage renal disease.

Eur J Appl Physiol 2022 Jan 20. Epub 2022 Jan 20.

Institute for Health and Sport, Victoria University, Melbourne, Australia.

Purpose: The cardiac T-wave peak-to-end interval (T) is thought to reflect dispersion in ventricular repolarisation, with abnormalities in T 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 T with exercise.

Methods: Serial ECGs (T, T/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 (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 T (110 ± 8 vs. 87 ± 5 ms, respectively, p = 0.03) and an increase in T/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 T 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 T/QT ratio in healthy participants and ESRD patients.

Conclusions: T and T/QT ratio are predicted by [K] during exercise. Low [K] during recovery from exercise was associated with increased T and T/QT, indicating accentuated dispersion of ventricular repolarisation. The findings suggest that variations in [K] with physical exertion may unmask electrophysiological vulnerabilities to arrhythmia.
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http://dx.doi.org/10.1007/s00421-021-04870-7DOI Listing
January 2022

Celebrities in the heart, strangers in the pancreatic beta cell: Voltage-gated potassium channels K 7.1 and K 11.1 bridge long QT syndrome with hyperinsulinaemia as well as type 2 diabetes.

Acta Physiol (Oxf) 2022 Jan 6:e13781. Epub 2022 Jan 6.

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Voltage-gated potassium (K ) 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 7.1, and KCNH2 (hERG), encoding K 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 7.1 and K 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.
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http://dx.doi.org/10.1111/apha.13781DOI Listing
January 2022

Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol.

Diabetes Care 2022 Jan;45(1):232-240

30Collaborative Studies Coordinating Center, Department of Biostatistics, The University of North Carolina at Chapel Hill, NC.

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.
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http://dx.doi.org/10.2337/dc21-1284DOI Listing
January 2022

DeepFake electrocardiograms using generative adversarial networks are the beginning of the end for privacy issues in medicine.

Sci Rep 2021 11 9;11(1):21896. Epub 2021 Nov 9.

University of Copenhagen, 2200, Copenhagen N, Denmark.

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.
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http://dx.doi.org/10.1038/s41598-021-01295-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8578227PMC
November 2021

Severity of congenital long QT syndrome disease manifestation and risk of depression, anxiety, and mortality: a nationwide study.

Europace 2021 Oct 15. Epub 2021 Oct 15.

Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.

Aims: We examined if a congenital long QT syndrome (cLQTS) diagnosis and severity of cLQTS disease manifestation was associated with increased risk of depression, anxiety, and all-cause mortality.

Methods And Results: All patients with known cLQTS in Denmark were identified using nationwide registries and specialized inherited cardiac disease clinics (1994-2016) and followed for up to 3 years after their cLQTS diagnosis. Risk factors for depression, anxiety, and all-cause mortality were determined using multivariable Cox proportional-hazards regression. An age- and sex-matched control population was identified (matching 1:4). Overall, 589 patients with cLQTS were identified of which 119/589 (20.2%) developed depression or anxiety during follow-up compared with 302/2356 (12.8%) from the control population (P < 0.001). Severity of cLQTS disease manifestation was identified for 324/589 (55%) of patients with cLQTS; 162 were asymptomatic, 119 had ventricular tachycardia (VT)/syncope, and 43 had aborted sudden cardiac death (aSCD). In multivariable models, patients with aSCD, VT/syncope, or unspecified cLQTS disease manifestation had a higher risk of developing depression or anxiety compared with the control population (hazard ratio [HR]=2.4, 95% confidence interval [CI]: 1.1-5.1; HR = 1.9, 95% CI: 1.2-3.0; HR = 1.6, 95% CI: 1.1-2.3, respectively). Asymptomatic patients had similar risk of developing depression or anxiety as the control population (HR = 1.2, 95% CI: 0.8-1.9). During follow-up, 10/589 (1.7%) patients with cLQTS died compared with 27/2356 (1.1%) from the control population (P = 0.5). Furthermore, 4/10 who died had developed depression or anxiety.

Conclusion: A severe cLQTS disease manifestation was associated with a greater risk of depression or anxiety. All-cause mortality for patients with cLQTS was low.
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http://dx.doi.org/10.1093/europace/euab252DOI Listing
October 2021

Effect of moderate potassium-elevating treatment in long QT syndrome: the TriQarr Potassium Study.

Open Heart 2021 09;8(2)

Department of Cardiology, Herlev-Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.

Background: In 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.

Methods: Patients with LQTS with a disease-causing or variant were included. In addition to usual beta-blocker treatment, patients were prescribed (1) 50 mg spironolactone () or (2) 100 mg spironolactone and 3 g potassium chloride per day (). Electrocardiographic measures were obtained at baseline and after 7 days of treatment.

Results: Twenty 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.

Conclusion: In 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 Number: NCT03291145.
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http://dx.doi.org/10.1136/openhrt-2021-001670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449979PMC
September 2021

Effect of hydroxychloroquine on the cardiac ventricular repolarization: A randomized clinical trial.

Br J Clin Pharmacol 2021 Jul 30. Epub 2021 Jul 30.

Centre for Human Drug Research, Leiden, The Netherlands.

Aims: Hydroxychloroquine has been suggested as possible treatment for severe acute respiratory syndrome-coronavirus-2. Studies reported an increased risk of QTcF-prolongation after treatment with hydroxychloroquine. The aim of this study was to analyse the concentration-dependent effects of hydroxychloroquine on the ventricular repolarization, including QTcF-duration and T-wave morphology.

Methods: Twenty young (≤30 y) and 20 elderly (65-75 y) 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. Electrocardiograms (ECGs) were recorded as triplicate at baseline and 4 postdose 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, were analysed with a prespecified 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 = .09, .34, .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 (200 ng/mL). There were no associations between hydroxychloroquine concentration and the T-wave morphology (P = .34 for morphology combination score). 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.
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http://dx.doi.org/10.1111/bcp.15013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444885PMC
July 2021

Age-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome loss-of-function mutation Kcnq1-A340V.

Sci Rep 2021 06 10;11(1):12253. Epub 2021 Jun 10.

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.

Loss-of-function (LoF) mutations in KCNQ1, encoding the voltage-gated K channel K7.1, lead to long QT syndrome 1 (LQT1). LQT1 patients also present with post-prandial hyperinsulinemia and hypoglycaemia. In contrast, KCNQ1 polymorphisms are associated with diabetes, and LQTS patients have a higher prevalence of diabetes. We developed a mouse model with a LoF Kcnq1 mutation using CRISPR-Cas9 and hypothesized that this mouse model would display QT prolongation, increased glucose-stimulated insulin secretion and allow for interrogation of K7.1 function in islets. Mice were characterized by electrocardiography and oral glucose tolerance tests. Ex vivo, islet glucose-induced insulin release was measured, and beta-cell area quantified by immunohistochemistry. Homozygous mice had QT prolongation. Ex vivo, glucose-stimulated insulin release was increased in islets from homozygous mice at 12-14 weeks, while beta-cell area was reduced. Non-fasting blood glucose levels were decreased at this age. In follow-up studies 8-10 weeks later, beta-cell area was similar in all groups, while glucose-stimulated insulin secretion was now reduced in islets from hetero- and homozygous mice. Non-fasting blood glucose levels had normalized. These data suggest that K7.1 dysfunction is involved in a transition from hyper- to hyposecretion of insulin, potentially explaining the association with both hypoglycemia and hyperglycemia in LQT1 patients.
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http://dx.doi.org/10.1038/s41598-021-90452-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192901PMC
June 2021

Explaining deep neural networks for knowledge discovery in electrocardiogram analysis.

Sci Rep 2021 05 26;11(1):10949. Epub 2021 May 26.

University of Copenhagen, 2200, Copenhagen N, Denmark.

Deep learning-based tools may annotate and interpret medical data more quickly, consistently, and accurately than medical doctors. However, as medical doctors are ultimately responsible for clinical decision-making, any deep learning-based prediction should be accompanied by an explanation that a human can understand. We present an approach called electrocardiogram gradient class activation map (ECGradCAM), which is used to generate attention maps and explain the reasoning behind deep learning-based decision-making in ECG analysis. Attention maps may be used in the clinic to aid diagnosis, discover new medical knowledge, and identify novel features and characteristics of medical tests. In this paper, we showcase how ECGradCAM attention maps can unmask how a novel deep learning model measures both amplitudes and intervals in 12-lead electrocardiograms, and we show an example of how attention maps may be used to develop novel ECG features.
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http://dx.doi.org/10.1038/s41598-021-90285-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154909PMC
May 2021

A Phase 1 Study to Investigate the Effects of Cortexolone 17α-Propionate, Also Known as Clascoterone, on the QT Interval Using the Meal Effect to Demonstrate ECG Assay Sensitivity.

Clin Pharmacol Drug Dev 2021 06 3;10(6):572-581. Epub 2021 May 3.

St George's, University of London, London, United Kingdom.

Cortexolone 17α-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 17α-propionate was found to have a weak inhibitory effect on human Ether-à-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 17α-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 17α-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 17α-propionate and its metabolite/degradation product had no effect on the QTc interval in the concentration range tested.
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http://dx.doi.org/10.1002/cpdd.935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251570PMC
June 2021

The Role of Leptin in Fetal Growth during Pre-Eclampsia.

Int J Mol Sci 2021 Apr 27;22(9). Epub 2021 Apr 27.

Department of Neonatology, University Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.

Leptin is secreted by the placenta and has a multi-facetted role in the regulation of functions related to pregnancy. Metabolic disorders and insufficient homeostatic compensatory mechanisms involving leptin during pregnancy play a decisive role in the development of pre-eclampsia (PE) and give rise to compromised intrauterine growth conditions and aberrant birth weight of offspring. This review was compiled to elucidate the metabolic background of PE and its relationship with adverse intrauterine growth conditions through the examination of leptin as well as to describe possible mechanisms linking leptin to fetal growth restriction. This review illustrates that leptin in PE is dysregulated in maternal, fetal, and placental compartments. There is no single set of unifying mechanisms within the spectrum of PE, and regulatory mechanisms involving leptin are specific to each situation. We conclude that dysregulated leptin is involved in fetal growth at many levels through complex interactions with parallel pregnancy systems and probably throughout the entirety of pregnancy.
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http://dx.doi.org/10.3390/ijms22094569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123779PMC
April 2021

Electrocardiographic T-wave morphology and risk of mortality.

Int J Cardiol 2021 04 13;328:199-205. Epub 2020 Dec 13.

Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Background: Electrocardiographic T-wave morphology is used in drug safety studies as an adjunct to the QT 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.

Methods: We 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, QT-prolonging drugs, diabetes, ischemic heart disease, hypertension, and congestive heart failure.

Results: 270,039 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.

Conclusions: In 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.
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http://dx.doi.org/10.1016/j.ijcard.2020.12.016DOI Listing
April 2021

A novel approach for obtaining 12-lead electrocardiograms in horses.

J Vet Intern Med 2021 Jan 4;35(1):521-531. Epub 2020 Dec 4.

Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.

Background: In equine medicine, 12-lead electrocardiograms (ECGs) rarely are used, which may in part be a result of shortcomings in the existing guidelines for obtaining 12-lead ECGs in horses. The guidelines recommend placing the limb leads on the extremities, which is inappropriate because the ventricular mean electrical axis is then perpendicular to the limb leads, leading to large variations in ECG configuration even among healthy horses. From an electrophysiological point of view, the leads instead should be parallel to the electrical axis to minimize variability.

Objective: Develop an improved method for obtaining 12-lead ECGs in horses based on electrophysiology and cardiac electrical vectors relevant to horses.

Animals: Thirty-five healthy Standardbred horses.

Methods: Two ECGs obtained at rest; 1 ECG with the electrodes placed according to the method developed in the present study, the Copenhagen method, and 1 ECG following existing guidelines.

Results: In the Copenhagen method, we repositioned the limb electrodes to the thorax to better capture the electrical activity of the heart. Variation in the mean electrical axis decreased dramatically with the Copenhagen method (SD decreased from 24.6° to 1.6°, P < .001). Consequently, this new method provided stable ECGs with repeatable configurations.

Conclusions And Clinical Importance: With this novel method, the ECG is recorded with respect to the electric axis to fully realize the potential of 12-lead ECG in horses. The Copenhagen method delivered more consistent and reliable ECG recordings compared to existing guidelines. The Copenhagen method potentially allows for expanded use of 12-lead ECGs in equine medicine.
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http://dx.doi.org/10.1111/jvim.15980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848388PMC
January 2021

Frequency of Long QT in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine: A Meta-analysis.

Int J Antimicrob Agents 2020 Dec 24;56(6):106212. Epub 2020 Oct 24.

Discipline of Medical Gerontology, Mercer's Institute for Successful Ageing, St James's Hospital, Dublin, Ireland; Global Brain Health Institute, Trinity College Dublin, Ireland.

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<120 ms) or QTc≥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.
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http://dx.doi.org/10.1016/j.ijantimicag.2020.106212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584880PMC
December 2020

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

Genet Med 2021 01 7;23(1):47-58. Epub 2020 Sep 7.

Member of the European Reference Network for rare, low prevalence and/or complex diseases of the heart: ERN GUARD-Heart, Amsterdam, Netherlands.

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 × 10) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10). 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.
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http://dx.doi.org/10.1038/s41436-020-00946-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790744PMC
January 2021

Long QT syndrome type 1 and 2 patients respond differently to arrhythmic triggers: The TriQarr in vivo study.

Heart Rhythm 2021 02 31;18(2):241-249. Epub 2020 Aug 31.

Department of Cardiology, Herlev-Gentofte Hospital, University Hospital of Copenhagen, Herlev, Denmark.

Background: In patients with long QT syndrome (LQTS), swimming and loud noises have been identified as genotype-specific arrhythmic triggers in LQTS type 1 (LQTS1) and LQTS type 2 (LQTS2), respectively.

Objective: The purpose of this study was to compare LQTS group responses to arrhythmic triggers.

Methods: LQTS1 and LQTS2 patients were included. Before and after beta-blocker intake, electrocardiograms were recorded as participants (1) were exposed to a loud noise of ∼100 dB; and (2) had their face immersed into cold water.

Results: Twenty-three patients (9 LQTS1, 14 LQTS2) participated. In response to noise, LQTS groups showed similarly increased heart rate, but LQTS2 patients had corrected QT interval (Fridericia formula) (QTcF) prolonged significantly more than LQTS1 patients (37 ± 8 ms vs 15 ± 6 ms; P = .02). After intake of beta-blocker, QTcF prolongation in LQTS2 patients was significantly blunted and similar to that of LQTS1 patients (P = .90). In response to simulated diving, LQTS groups experienced a heart rate drop of ∼28 bpm, which shortened QTcF similarly in both groups. After intake of beta-blockers, heart rate dropped to 28 ± 2 bpm in LQTS1 patients and 20 ± 3 bpm in LQTS2, resulting in a slower heart rate in LQTS1 compared with LQTS2 (P = .01). In response, QTcF shortened similarly in LQTS1 and LQTS2 patients (57 ± 9 ms vs 36 ± 7 ms; P = .10).

Conclusion: When exposed to noise, LQTS2 patients had QTc prolonged significantly more than did LQTS1 patients. Importantly, beta-blockers reduced noise-induced QTc prolongation in LQTS2 patients, thus demonstrating the protective effect of beta-blockers. In response to simulated diving, LQTS groups responded similarly, but a slower heart rate was observed in LQTS1 patients during simulated diving after beta-blocker intake.
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http://dx.doi.org/10.1016/j.hrthm.2020.08.017DOI Listing
February 2021

Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation.

Circ Genom Precis Med 2020 10 21;13(5):387-395. Epub 2020 Aug 21.

DZHK (German Center for Cardiovascular Research), partner site Greifswald, Germany (A.T., U.V., M.D., S.B.F.).

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 (, , , , , , , ). The top variants at known sarcomere genes () were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, and ) 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.
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http://dx.doi.org/10.1161/CIRCGEN.119.002874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578098PMC
October 2020

Electrocardiography in euthyroid individuals: a Danish general population study.

Minerva Endocrinol 2020 Jul 23. Epub 2020 Jul 23.

Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark -

Background: Thyroid hormones within the euthyroid range have been linked to mortality and differences in heart rate. However, some relations between thyroid hormone concentration and various electrocardiographic measurements remain unassessed. We aimed to investigate the association between thyroid hormone concentrations within the euthyroid range and different electrocardiographic markers in people free of thyroid disease.

Methods: We obtained electrocardiograms (ECG) and blood samples of free T4, total T3, and thyrotropin (TSH) in 20,852 subjects from the general population (the GESUS study). Relations between concentrations of TSH, free T4, and total T3 and heart rate, QTc, QRS duration, PR interval, P-wave duration and T-wave morphology were assessed in a multivariate adjusted linear model stratified by sex.

Results: Roughly half of the 18,046 included participants with thyroid hormone measurements within euthyroid range were men, and the average age was 56 years. Heart rate increased with concentrations of T3 (6.4 bpm/nM, p<0.001 in women and 5.3 bpm/nM, p<0.001 in men) and T4 (3.7 bpm/10pM, p<0.001 in women and 3.1 bpm/10pM, p<0.001 in men). We found no relation between TSH and heart rate. PR interval and QRS duration decreased with higher concentrations of T3 (all p<0.01). QTc increased with higher concentrations of T4 in men (5 ms/10pM), and T waves were flatter, more asymmetric and more often had notches with higher concentrations of T4 (all p≤0.01).

Conclusions: Thyroid hormone concentrations within the euthyroid range in people free of thyroid disease were associated with changes in the electrocardiogram in a general population.
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http://dx.doi.org/10.23736/S0391-1977.20.03170-3DOI Listing
July 2020

Early glycaemic changes after initiation of oral antidiabetic medication and risk of major adverse cardiovascular events: results from a large primary care population of patients with type 2 diabetes.

Eur Heart J Cardiovasc Pharmacother 2021 Nov;7(6):486-495

Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Building 9312, Juliane Maries Vej 20, 2100 Copenhagen, Denmark.

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 [<9 mmol/mol per 3 months (<0.8%)]. Pre-treatment HbA1C was categorized by the median, into levels of low (48-62 mmol/mol) and high (>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.
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http://dx.doi.org/10.1093/ehjcvp/pvaa072DOI Listing
November 2021

Evolutionary dissection of mtDNA hg H: a susceptibility factor for hypertrophic cardiomyopathy.

Mitochondrial DNA A DNA Mapp Seq Anal 2020 08 30;31(6):238-244. Epub 2020 Jun 30.

Department for Congenital Disorders, Statens Serum Institute, Copenhagen, Denmark.

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 ( = 170 and = 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 ( = 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.
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http://dx.doi.org/10.1080/24701394.2020.1782897DOI Listing
August 2020

P-wave indices as predictors of atrial fibrillation.

Ann Noninvasive Electrocardiol 2020 09 10;25(5):e12751. Epub 2020 Apr 10.

Department of Cardiology, Copenhagen University Hospital of Bispebjerg, Copenhagen, Denmark.

Background: P-wave duration (P ) and P-wave area (P ) have been linked to risk of atrial fibrillation (AF), but they do not improve the efficacy of Framingham AF risk score. We suggest the incorporation of both variables in one index, the P-wave area/P-wave duration (P ) index, which may be considered an expression of the average amplitude of the P wave that reflects aspects of P-wave morphology.

Objective: To assess the prognostic value of P-wave area/P-wave duration index (P index) in lead II together with other P-wave indices (PWIs) in incidence of AF in the Copenhagen Holter Study.

Methods: The study included 632 men and women, between 55 and 75 years with no apparent heart disease or AF. Baseline standard 12-lead Electrocardiography (ECGs) were analyzed manually.

Results: The median follow-up time was 14.7 (14.5;14.9) years. A total of 68 cases of AF and 233 cases of death were recorded. The restricted cubic spline method showed a U-shaped association between P and rate of AF. The lowest quintile of P index in lead II was associated with increased rate of AF, HR 2.80 (1.64-4.79). The addition of the new index to the Framingham model for AF improved the model in this population. The P in lead II in its lowest quintile was also associated with increased rate of AF, HR 2.16 (1.25-3.75), but did not improve the Framingham model. P and P-wave terminal force (PTF) were not significantly associated with AF.

Conclusion: A flat P wave as expressed by a small P index in lead II is associated with increased rate of incident AF beyond known AF risk factors.
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http://dx.doi.org/10.1111/anec.12751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507358PMC
September 2020

Gain-of-function mutation in the voltage-gated potassium channel gene KCNQ1 and glucose-stimulated hypoinsulinemia - case report.

BMC Endocr Disord 2020 Mar 13;20(1):38. Epub 2020 Mar 13.

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: The voltage-gated potassium channel Kv7.1 encoded by KCNQ1 is located in both cardiac myocytes and insulin producing beta cells. Loss-of-function mutations in KCNQ1 causes long QT syndrome along with glucose-stimulated hyperinsulinemia, increased C-peptide and postprandial hypoglycemia. The KCNE1 protein modulates Kv7.1 in cardiac myocytes, but is not expressed in beta cells. Gain-of-function mutations in KCNQ1 and KCNE1 shorten the action potential duration in cardiac myocytes, but their effect on beta cells and insulin secretion is unknown.

Case Presentation: Two patients with atrial fibrillation due to gain-of-function mutations in KCNQ1 (R670K) and KCNE1 (G60D) were BMI-, age-, and sex-matched to six control participants and underwent a 6-h oral glucose tolerance test (OGTT). During the OGTT, the KCNQ1 gain-of-function mutation carrier had 86% lower C-peptide response after glucose stimulation compared with matched control participants (iAUC = 34 pmol/l*min VS iAUC = 246 ± 71 pmol/l*min). The KCNE1 gain-of-function mutation carrier had normal C-peptide levels.

Conclusions: This case story presents a patient with a gain-of-function mutation KCNQ1 R670K with low glucose-stimulated C-peptide secretion, additionally suggesting involvement of the voltage-gated potassium channel KCNQ1 in glucose-stimulated insulin regulation.
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http://dx.doi.org/10.1186/s12902-020-0513-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069191PMC
March 2020

Long QT syndrome is associated with an increased burden of diabetes, psychiatric and neurological comorbidities: a nationwide cohort study.

Open Heart 2019;6(2):e001161. Epub 2019 Oct 28.

Department of Cardiology, Herlev-Gentofte Hospital, University Hospital of Copenhagen, Copenhagen, Denmark.

Objective: Studies have suggested a shared genetic aetiology between congenital long QT syndrome (LQTS) and diabetes, epilepsy and mental disorders. We investigated the prevalence of metabolic, neurological and psychiatric comorbidities in LQTS patients.

Methods: This retrospective cohort study was based on data from nationwide Danish registries, 2003-2017. LQTS patients were matched 1:5 with controls on sex and age.

Results: We matched 463 LQTS patients with 2315 controls from the background population. Mean age was 35.7 (SD 21.0) years, and 38% were males in both groups. LQTS patients had a higher prevalence of atrial fibrillation (6.5% vs 2.3%, p<0.001), diabetes (3.7% vs 1.8 %, p=0.011) and hearing loss (3.2% vs 1.7%, p=0.027). LQTS patients had a higher prevalence of psychiatric disorders overall (13.0% vs 9.1%, p=0.01) but the difference could not be attributed to a specific psychiatric disease subgroup. LQTS patients had a higher prevalence of neurological disorders (22.0% vs 13.2%, p<0.001), largely driven by epilepsy (6.7% vs 1.6%, p<0.001). In 20/27 (74%) of the LQTS patients, the epilepsy diagnosis did not reappear in the registries after the LQTS diagnosis was established.

Conclusions: In this nationwide cohort, patients with LQTS had a significantly increased burden of diabetes, neurological and psychiatric comorbidities, compared with the background population. The higher prevalence of neurological comorbidities was largely driven by epilepsy, despite a high rate of potentially misdiagnosed patients prior to LQTS diagnosis. Our data support that LQTS may be considered a multiorgan disease and suggest that patient management should be adjusted accordingly.
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http://dx.doi.org/10.1136/openhrt-2019-001161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827808PMC
February 2021

The CardioSynchroGram: A method to visualize and quantify ventricular dyssynchrony.

J Electrocardiol 2019 Nov - Dec;57S:S45-S50. Epub 2019 Oct 20.

CardioTech Research Group, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.

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http://dx.doi.org/10.1016/j.jelectrocard.2019.09.020DOI Listing
May 2021

The relationship between serum potassium concentrations and electrocardiographic characteristics in 163,547 individuals from primary care.

J Electrocardiol 2019 Nov - Dec;57:104-111. Epub 2019 Sep 4.

Unit of Epidemiology and Biostatistics, Aalborg University Hospital, Søndre Skovvej 15, 9000 Aalborg, Denmark.

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 μV 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 μV 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.
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http://dx.doi.org/10.1016/j.jelectrocard.2019.09.005DOI Listing
June 2021

Effect of diabetes duration on the relationship between glycaemic control and risk of death in older adults with type 2 diabetes.

Diabetes Obes Metab 2020 02 18;22(2):231-242. Epub 2019 Nov 18.

Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Copenhagen, Denmark.

Aim: To investigate the effect of diabetes duration on glycaemic control, measured using mean glycated haemoglobin (HbA1c) level, and mortality risk within different age, sex and clinically relevant, comorbidity-defined subgroups in an elderly population with type 2 diabetes (T2D).

Methods: We studied older (≥65 years) primary care patients with T2D, who had three successive annual measurements of HbA1c taken between 2005 and 2013. The primary exposure was the mean of all three HbA1c measurements. Follow-up began on the date of the third measurement. Individual mean HbA1c levels were categorized into clinically relevant groups (<6.5% [<48 mmol/mol]; 6.5%-6.9% [48-52 mmol/mol]; 7%-7.9% [53-63 mmol/mol]; 8%-8.9% [64-74 mmol/mol]; and ≥9% [≥75 mmol/mol]). We used multiple Cox regression to study the effect of glycaemic control on the hazard of all-cause mortality, adjusted for age, sex, use of concomitant medication, and age- and disease-related comorbidities.

Results: A total of 9734 individuals were included. During a median (interquartile range) follow-up of 7.3 (4.6-8.7) years, 3320 individuals died. We found that the effect of mean HbA1c on all-cause mortality depended on the duration of diabetes (P for interaction <.001). For individuals with short diabetes duration (<5 years), the risk of death increased with poorer glycaemic control (increasing HbA1c), whereas for individuals with longstanding diabetes (≥5 years), we found a J-shaped association, where a mean HbA1c level between 6.5% and 7.9% [48 and 63 mmol/mol] was associated with the lowest risk of death. For individuals with longstanding diabetes, both low (<6.5% [<48 mmol/mol]; hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.07-1.37, P = .002) and high mean HbA1c levels (≥9.0% [≥75 mmol/mol]; HR 1.60, 95% CI 1.28-1.99, P < .001) were associated with an increased risk of death. We also calculated 5-year absolute risks of all-cause mortality, separately for short and long diabetes duration, and found similar risk patterns across different age groups, sex and comorbidity strata.

Conclusions: In elderly individuals with T2D, the effect of glycaemic control (measured by HbA1c) on all-cause mortality depended on the duration of diabetes. Of particular clinical importance, we found that strict glycaemic control was associated with an increased risk of death among individuals with long (≥ 5 years) diabetes duration. Conversely, for individuals with short diabetes duration, strict glycaemic control was associated with the lowest risk of death. These results indicate that tight glycemic control may be beneficial in people with short duration of diabetes, whereas a less stringent target may be warranted with longer diabetes exposure.
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http://dx.doi.org/10.1111/dom.13891DOI Listing
February 2020

Effects of Calcium, Magnesium, and Potassium Concentrations on Ventricular Repolarization in Unselected Individuals.

J Am Coll Cardiol 2019 06;73(24):3118-3131

Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.

Background: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions.

Objectives: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population.

Methods: Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs.

Results: Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals.

Conclusions: The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms.
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http://dx.doi.org/10.1016/j.jacc.2019.03.519DOI Listing
June 2019

Long-term proarrhythmic pharmacotherapy among patients with congenital long QT syndrome and risk of arrhythmia and mortality.

Eur Heart J 2019 10;40(37):3110-3117

Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen Health Science Partners, Blegdamsvej 9, Copenhagen, Denmark.

Aims: It is Class I recommendation that congenital long QT syndrome (cLQTS) patients should avoid drugs that can cause torsades de pointes (TdP). We determined use of TdP risk drugs after cLQTS diagnosis and associated risk of ventricular arrhythmia and all-cause mortality.

Methods And Results: Congenital long QT syndrome patients (1995-2015) were identified from four inherited cardiac disease clinics in Denmark. Individual-level linkage of nation-wide registries was performed to determine TdP risk drugs usage (www.crediblemeds.org) and associated risk of ventricular arrhythmias and all-cause mortality. Risk analyses were performed using Cox-hazards analyses. During follow-up, 167/279 (60%) cLQTS patients were treated with a TdP risk drug after diagnosis. Most common TdP risk drugs were antibiotics (34.1%), proton-pump inhibitors (15.0%), antidepressants (12.0%), and antifungals (10.2%). Treatment with a TdP risk drug decreased 1 year after diagnosis compared with 1 year before (28.4% and 23.2%, respectively, P < 0.001). Five years after diagnosis, 33.5% were in treatment (P < 0.001). Risk factors for TdP risk drug treatment were age at diagnosis (5-year increment) [hazard ratio (HR) = 1.07, confidence interval (CI) 1.03-1.11] and previous TdP risk drug treatment (HR = 2.57, CI 1.83-3.61). During follow-up, nine patients were admitted with ventricular arrhythmia (three were in treatment with a TdP risk drug). Eight patients died (four were in treatment with a TdP risk drug). No significant association between TdP risk drug use and ventricular arrhythmias or all-cause mortality was found (P = 0.53 and P = 0.93, respectively), but events were few.

Conclusion: Torsades de pointes risk drug usage was common among cLQTS patients after time of diagnosis and increased over time. A critical need for more awareness in prescribing patterns for this high-risk patient group is needed.
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http://dx.doi.org/10.1093/eurheartj/ehz228DOI Listing
October 2019

Genome-wide association study identifies locus at chromosome 2q32.1 associated with syncope and collapse.

Cardiovasc Res 2020 01;116(1):138-148

Laboratory for Molecular Cardiology, Department of Cardiology, The Heart Centre, Rigshospitalet (Copenhagen University Hospital), Copenhagen, Denmark.

Aims: Syncope is a common condition associated with frequent hospitalization or visits to the emergency department. Family aggregation and twin studies have shown that syncope has a heritable component. We investigated whether common genetic variants predispose to syncope and collapse.

Methods And Results: We used genome-wide association data on syncope on 408 961 individuals with European ancestry from the UK Biobank study. In a replication study, we used the Integrative Psychiatric Research Consortium (iPSYCH) cohort (n = 86 189), to investigate the risk of incident syncope stratified by genotype carrier status. We report on a genome-wide significant locus located on chromosome 2q32.1 [odds ratio = 1.13, 95% confidence interval (CI) 1.10-1.17, P = 5.8 × 10-15], with lead single nucleotide polymorphism rs12465214 in proximity to the gene zinc finger protein 804a (ZNF804A). This association was also shown in the iPSYCH cohort, where homozygous carriers of the C allele conferred an increased hazard ratio (1.30, 95% CI 1.15-1.46, P = 1.68 × 10-5) of incident syncope. Quantitative polymerase chain reaction analysis showed ZNF804A to be expressed most abundantly in brain tissue.

Conclusion: We identified a genome-wide significant locus (rs12465214) associated with syncope and collapse. The association was replicated in an independent cohort. This is the first genome-wide association study to associate a locus with syncope and collapse.
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http://dx.doi.org/10.1093/cvr/cvz106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918066PMC
January 2020

Reappraisal of variants previously linked with sudden infant death syndrome: results from three population-based cohorts.

Eur J Hum Genet 2019 09 1;27(9):1427-1435. Epub 2019 May 1.

Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

We aimed to investigate the pathogenicity of cardiac ion channel variants previously associated with SIDS. We reviewed SIDS-associated variants previously reported in databases and the literature in three large population-based cohorts; The ExAC database, the Inter99 study, and the UK Biobank (UKBB). Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Of the 92 SIDS-associated variants, 59 (64%) were present in ExAC, 18 (20%) in Inter99, and 24 (26%) in UKBB. Using the Inter99 cohort, we found no difference in J-point amplitude and QTc-interval between carriers and non-carriers for 14/18 variants. There was no difference in the risk of syncope (P = 0.32), malignant ventricular arrhythmia (P = 0.96), and all-cause mortality (P = 0.59) between carriers and non-carriers. The ACMG guidelines reclassified 75% of all variants as variant-of-uncertain significance, likely benign, and benign. We identified ~2/3 of variants previously associated with SIDS and found no significant associations with electrocardiographic traits, syncope, malignant ventricular arrhythmia, or all-cause mortality. These data indicate that many of these variants are not highly penetrant, monogenic causes of SIDS and underline the importance of frequent reappraisal of genetic variants to avoid future misdiagnosis.
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http://dx.doi.org/10.1038/s41431-019-0416-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777469PMC
September 2019
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