Publications by authors named "Jonas Ghouse"

25 Publications

  • Page 1 of 1

Associations between primary care electrocardiography and non-Alzheimer dementia.

J Stroke Cerebrovasc Dis 2022 Jul 10;31(9):106640. Epub 2022 Jul 10.

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

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<0.001), shorter QRS duration (HR=1.07 pr. 10 ms [1.05-1.09], p<0.001), elevated J-amplitude (HR=1.16 pr. mm [1.08-1.24], p<0.001), decreased T-peak amplitude (HR=1.02 pr. mm [1.01-1.04], p=0.002), and increased QTc (HR=1.08 pr. 20 ms [1.05-1.10], p<0.001) were associated with an increased rate of non-AD. Atrial fibrillation on the ECG (HR=1.18 [1.08-1.28], p<0.001) Sokolow-Lyon index > 35 mm (HR=1.31 [1.18-1.46], p<0.001) and borderline (HR=1.18 [1.11-1.26], p<0.001) or abnormal (HR=1.40 [1.27-1.55], p<0.001) QRS-T angle were also associated with an increased rate of non-AD. Upon addition of ECG markers to the Cox model, 5-year and 10-year C-statistic (AUC) improved significantly (delta-AUC, 0.36 [0.18-0.50] and 0.20 [0.03-0.35] %-points, respectively).

Conclusions: 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.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2022.106640DOI Listing
July 2022

Polygenic risk score for ACE-inhibitor-associated cough based on the discovery of new genetic loci.

Eur Heart J 2022 Jun 25. Epub 2022 Jun 25.

Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Building 9312, Henrik Harpestrengs Vej 4C, 2100 Copenhagen, Denmark.

Aims: To search for sequence variants associated with ACEi discontinuation and to test their association with ACEi-associated adverse drug reactions (ADRs).

Methods And Results: A genome-wide association study (GWAS) on ACEi discontinuation was conducted, including 33 959 ACEi-discontinuers and 44 041 controls. Cases were defined as persons who switched from an ACEi treatment to an angiotensin receptor blocker. Controls were defined as persons who continued ACEi treatment for at least 1 year. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed for ACEi discontinuation risk by mixed model regression analysis. Summary statistics from the individual cohorts were meta-analyzed with a fixed-effects model. To test for association with specific ACEi-associated ADRs, any genome-wide significant (P < 5 × 10-8) ACEi discontinuation variants was tested for association with ACEi-associated cough and angioedema. A polygenetic risk score (PRS) based on ACEi discontinuation GWAS data was constructed and tested for association with ACEi-associated cough and angioedema in two population-based samples. In total, seven genetic genome-wide loci were identified, of which six were previously unreported. The strongest association with ACEi discontinuation was at 20q13.3 (NTSR1; OR: 1.21; 95% CI: 1.17-1.24; P = 2.1 × 10-34). Five of seven lead variants were associated with ACEi-associated cough, whereas none were associated with ACEi-associated angioedema. The ACEi discontinuation PRS was associated with ACEi-associated cough in a dose-response manner but not with ACEi-associated angioedema. ACEi discontinuation was genetically correlated with important causes for cough, including gastro-esophageal reflux disease, allergic rhinitis, hay fever, and asthma, which indicates partly shared genetic underpinning between these traits.

Conclusion: This study showed the advantage of using prescription patterns to discover genetic links with ADRs. In total, seven genetic loci that associated with ACEi discontinuation were identified. There was evidence of a strong association between our ADR phenotype and ACEi-associated cough. Taken together, these findings increase insight into the pathophysiological processes that underlie ACEi-associated ADRs.
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http://dx.doi.org/10.1093/eurheartj/ehac322DOI Listing
June 2022

Association of Common and Rare Genetic Variation in the 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Gene and Cataract Risk.

J Am Heart Assoc 2022 06 15;11(12):e025361. Epub 2022 Jun 15.

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

Background Results from animal models and observational studies have raised concerns regarding the potential cataractogenic effects of statin treatment. We investigated whether common and rare genetic variants in are associated with cataract risk, to gauge the likely long-term effects of statin treatment on lenticular opacities. Methods and Results We used genotyping data and exome sequencing data of unrelated European individuals in the UK Biobank to test the association between genetically proxied inhibition of and cataract risk. First, we constructed an genetic score consisting of 5 common variants weighted by their association with low-density lipoprotein cholesterol. Second, we analyzed exome sequencing data to identify carriers of predicted loss-of-function mutations in . Common and rare variants in aggregate were then tested for association with cataract and cataract surgery. In an analysis of >402 000 individuals, a 38.7 mg/dL (1 mmol/L) reduction in low-density lipoprotein C by the genetic score was associated with higher risk for cataract (odds ratio, 1.14 [95% CI, 1.00-1.39], =0.045) and cataract surgery (odds ratio, 1.25 [95% CI, 1.06-1.48], =0.009). Among 169 172 individuals with sequencing data, we identified 32 participants (0.02%), who carried a rare predicted loss-of-function variant. Compared with noncarriers, heterozygous carriers of predicted loss-of-function had a higher risk of developing cataract (odds ratio, 4.54 [95% CI, 1.96-10.53], =0.001) and cataract surgery (odds ratio, 5.27 [95% CI, 2.27-12.25]=5.37×10). In exploratory analyses, we found no significant association between genetically proxied inhibition of , or circulating low-density lipoprotein cholesterol levels (>0.05 for all) and cataract risk. Conclusions We found that genetically proxied inhibition of the gene mimicking long-term statin treatment associated with higher risk of cataract. Clinical trials with longer follow-up are needed to confirm these findings.
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http://dx.doi.org/10.1161/JAHA.122.025361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9238641PMC
June 2022

Effect of Loss-of-Function Genetic Variants in PCSK9 on Glycemic Traits, Neurocognitive Impairment, and Hepatobiliary Function.

Diabetes Care 2022 01;45(1):251-254

1Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Objective: To evaluate the association between PCSK9 predicted loss-of-function (pLoF) variants and glycemic traits, hepatobiliary function, and neurocognitive traits.

Research Design And Methods: We identified carriers of PCSK9 pLoF variants in UK Biobank exome sequencing data. We assessed the aggregate effects of these variants on lipid and lipoprotein traits, which served as a positive control. Association of PCSK9 pLoF carrier status and glycemic traits, hepatobiliary function, and neurocognitive traits was then evaluated as a measure for adverse effects.

Results: We identified 374 individuals carrying one of 41 unique PCSK9 pLoF variants. As expected, we found that PCSK9 pLoF carriers had significantly lower LDL cholesterol C levels (P = 7.4 × 10-55) and apolipoprotein B levels (P = 7.6 × 10-50) than did noncarriers. However, we found no significant associations between pLoF carrier status and glycemic traits, hepatobiliary function, and neurocognitive traits (P > 0.05).

Conclusions: Our results do not support adverse effects of PCSK9 pLoF variants on glycemic traits, hepatobiliary function, or neurocognitive traits.
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http://dx.doi.org/10.2337/dc21-0955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8753759PMC
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

Fascicular heart blocks and risk of adverse cardiovascular outcomes: Results from a large primary care population.

Heart Rhythm 2022 02 19;19(2):252-259. Epub 2021 Oct 19.

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

Background: Fascicular heart blocks can progress to complete heart blocks, but this risk has not been evaluated in a large general population.

Objective: The purpose of this study was to investigate the association between various types of fascicular blocks diagnosed by electrocardiographic (ECG) readings and the risk of incident higher degree atrioventricular block (AVB), syncope, pacemaker implantation, and death.

Methods: We studied primary care patients referred for ECG recording between 2001 and 2015. Cox regression models were used to estimate hazard ratios (HRs) as well as absolute risks of cardiovascular outcomes.

Results: Of 358,958 primary care patients (median age 54 years; 55% women), 13,636 (3.8%) had any type of fascicular block. Patients were followed up to 15.9 years. We found increasing HRs of incident syncope, pacemaker implantation, and third-degree AVB with increasing complexity of fascicular block. Compared with no block, isolated left anterior fascicular block (LAFB) was associated with 0%-2% increased 10-year risk of developing third-degree AVB (HR 1.6; 95% confidence interval [CI] 1.25-2.05), whereas right bundle branch block combined with LAFB and first-degree AVB was associated with up to 23% increased 10-year risk (HR 11.0; 95% CI 7.7-15.7), depending on age and sex group. Except for left posterior fascicular block (HR 2.09; 95% CI 1.87-2.32), we did not find any relevant associations between fascicular block and death.

Conclusion: We found that higher degrees of fascicular blocks were associated with increasing risk of syncope, pacemaker implantation, and complete heart block, but the association with death was negligible.
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http://dx.doi.org/10.1016/j.hrthm.2021.09.041DOI Listing
February 2022

Association of Variants Near the Bradykinin Receptor B Gene With Angioedema in Patients Taking ACE Inhibitors.

J Am Coll Cardiol 2021 08;78(7):696-709

Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Laboratory for Molecular Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: Angioedema is a rare but potentially life-threatening adverse reaction associated with angiotensin-converting enzyme (ACE) inhibitors. Identification of potential genetic factors related to this adverse event may help identify at-risk patients.

Objectives: The aim of this study was to identify genetic factors associated with ACE inhibitor-associated angioedema.

Methods: A genomewide association study involving patients of European descent, all taking ACE inhibitors, was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as subjects with angioedema events and filled prescriptions for ACE inhibitors ≤180 days before the events. Control subjects were defined as those with continuous treatment with ACE inhibitors without any history of angioedema. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for angioedema risk using logistic mixed model regression analysis. Summary statistics from the discovery and replication cohorts were analyzed using a fixed-effects meta-analysis model.

Results: The discovery cohort consisted of 462 cases and 53,391 ACE inhibitor-treated control subjects. The replication cohort consisted of 142 cases and 1,345 ACE inhibitor-treated control subjects. In the discovery cohort, 1 locus, residing at chromosome 14q32.2, was identified that associated with angioedema at the genomewide significance level of P <5 × 10. The lead variant at this locus, rs34485356, is an intergenic variant located 60 kb upstream of BDKRB2 (OR: 1.62; 95% CI: 1.38 to 1.90; P = 4.3 × 10). This variant was validated in our replication cohort with a similar direction and effect size (OR: 1.60; 95% CI: 1.13 to 2.25; P = 7.2 × 10). We found that carriers of the risk allele had significantly lower systolic (-0.46 mm Hg per T allele; 95% CI: -0.83 to -0.10; P = 0.013) and diastolic (-0.26 mm Hg per T allele; 95% CI: -0.46 to -0.05; P = 0.013) blood pressure.

Conclusions: In this genomewide association study involving individuals treated with ACE inhibitors, we found that common variants located in close proximity to the bradykinin receptor B gene were associated with increased risk for ACE inhibitor-related angioedema.
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http://dx.doi.org/10.1016/j.jacc.2021.05.054DOI Listing
August 2021

Genome-wide association study identifies 18 novel loci associated with left atrial volume and function.

Eur Heart J 2021 11;42(44):4523-4534

Laboratory for Molecular Cardiology, Department of Cardiology, Heart Centre, Rigshospitalet, University Hospital of Copenhagen, Henrik Harpestrengs Vej 4C, 2100 Copenhagen, Denmark.

Aims: Left atrial (LA) volume and function impose significant impact on cardiovascular pathogenesis if compromised. We aimed at investigating the genetic architecture of LA volume and function using cardiac magnetic resonance imaging data.

Methods And Results: We used the UK Biobank, which is a large prospective population study with available phenotypic and genetic data. On a subset of 35 658 European individuals, we performed genome-wide association studies on five volumetric and functional LA variables, generated using a machine learning algorithm. In total, we identified 18 novel genetic loci, mapped to genes with known roles in cardiomyopathy (e.g. MYO18B, TTN, DSP, ANKRD1) and arrhythmia (e.g. TTN, CASQ2, MYO18B, C9orf3). We observed high genetic correlation between LA volume and function and stroke, which was most pronounced for LA passive emptying fraction (rg = 0.40, P = 4 × 10-6). To investigate whether the genetic risk of atrial fibrillation (AF) is associated with LA traits that precede overt AF, we produced a polygenetic risk score for AF. We found that polygenetic risk for AF is associated with increased LA volume and decreased LA function in participants without AF [LAmax 0.25 (mL/m2)/standard deviation (SD), 95% confidence interval (CI) (0.15; 0.36), P = 5.13 × 10-6; LAmin 0.21 (mL/m2)/SD, 95% CI (0.15; 0.28), P = 1.86 × 10-10; LA active emptying fraction -0.35%/SD, 95% CI (-0.43; -0.26), P = 3.14 × 10-14].

Conclusion: We report on 18 genetic loci associated with LA volume and function and show evidence for several plausible candidate genes important for LA structure.
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http://dx.doi.org/10.1093/eurheartj/ehab466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633773PMC
November 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

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

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 11;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

Early-onset atrial fibrillation patients show reduced left ventricular ejection fraction and increased atrial fibrosis.

Sci Rep 2020 06 22;10(1):10039. Epub 2020 Jun 22.

Laboratory for Molecular Cardiology, Department of Cardiology, Centre for Cardiac, Vascular, Pulmonary and Infectious Diseases, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.

Atrial fibrillation (AF) has traditionally been considered an electrical heart disease. However, genetic studies have revealed that the structural architecture of the heart also play a significant role. We evaluated the functional and structural consequences of harboring a titin-truncating variant (TTNtv) in AF patients, using cardiac magnetic resonance (CMR). Seventeen early-onset AF cases carrying a TTNtv, were matched 1:1 with non-AF controls and a replication cohort of early-onset AF cases without TTNtv, and underwent CMR. Cardiac volumes and left atrial late gadolinium enhancement (LA LGE), as a fibrosis proxy, were measured by a blinded operator. Results: AF cases with TTNtv had significantly reduced left ventricular ejection fraction (LVEF) compared with controls (57 ± 4 vs 64 ± 5%, P < 0.001). We obtained similar findings in early-onset AF patients without TTNtv compared with controls (61 ± 4 vs 64 ± 5%, P = 0.02). We furthermore found a statistically significant increase in LA LGE when comparing early-onset AF TTNtv cases with controls. Using state-of-the-art CMR, we found that early-onset AF patients, irrespective of TTNtv carrier status, had reduced LVEF, indicating that early-onset AF might not be as benign as previously thought.
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http://dx.doi.org/10.1038/s41598-020-66671-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308347PMC
June 2020

Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation.

J Clin Med 2020 Jan 29;9(2). Epub 2020 Jan 29.

.Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and it is associated with an increased risk of heart failure, stroke, dementia, and death. Recently, titin-truncating variants (TTNtv), which are predominantly associated with dilated cardiomyopathy (DCM), were associated with early-onset AF. Furthermore, genome-wide association studies (GWAS) associated AF with other structural genes. In this study, we investigated whether early-onset AF was associated with loss-of-function variants in DCM-associated genes encoding cytoskeletal proteins. Using targeted sequencing, we examined a cohort of 527 Scandinavian individuals with early-onset AF and a control group of individuals free of AF ( = 383). The patients had onset of AF before 50 years of age, normal echocardiogram, and no other cardiovascular disease at onset of AF. We identified six individuals with rare loss-of-function variants in three different genes (dystrophin (), actin-associated protein (), and fukutin ()), of which two variants were novel. Loss-of-function variants in cytoskeletal genes were significantly associated with early-onset AF when patients were compared with controls ( = 0.044). Using publicly available GWAS data, we performed genetic correlation analyses between AF and 13 other traits, e.g., showing genetic correlation between AF and non-ischemic cardiomyopathy ( = 0.0003). Our data suggest that rare loss-of-function variants in cytoskeletal genes previously associated with DCM may have a role in early-onset AF, perhaps through the development of an atrial cardiomyopathy.
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http://dx.doi.org/10.3390/jcm9020372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074234PMC
January 2020

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

Clinical implications of electrocardiographic bundle branch block in primary care.

Heart 2019 08 25;105(15):1160-1167. Epub 2019 May 25.

Laboratory for Molecular Cardiology, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark.

Objectives: Electrocardiographic bundle branch block (BBB) is common but the prognostic implications in primary care are unclear. We sought to investigate the relationship between electrocardiographic BBB subtypes and the risk of cardiovascular (CV) outcomes in a primary care population free of major CV disease.

Methods: Retrospective cohort study of primary care patients referred for electrocardiogram (ECG) recording between 2001 and 2011. Cox regression models were used to estimate hazard ratios (HR) as well as absolute risks of CV outcomes based on various BBB subtypes.

Results: We included 202 268 individuals with a median follow-up period of 7.8 years (Inter-quartile range [IQR] 4.9-10.6). Left bundle branch block (LBBB) was associated with heart failure (HF) in both men (HR 3.96, 95% CI 3.30 to 4.76) and women (HR 2.51, 95% CI 2.15 to 2.94) and with CV death in men (HR 1.80, 95% CI 1.38 to 2.35). Right bundle branch block (RBBB) was associated with pacemaker implantation in both men (HR 3.26, 95% CI 2.74 to 3.89) and women (HR 3.69, 95% CI 2.91 to 4.67), HF in both sexes and weakly associated with CV death in men. Regarding LBBB, we found an increasing hazard of HF with increasing QRS-interval duration (HR 1.25, 95% CI 1.11 to 1.42 per 10 ms increase in men and HR 1.23, 95% CI 1.08 to 1.40 per 10 ms increase in women). Absolute 10-year risk predictions across age-specific and sex-specific subgroups revealed clinically relevant differences between having various BBB subtypes.

Conclusions: Opportunistic findings of BBB subtypes in primary care patients without major CV disease should be considered warnings of future HF and pacemaker implantation.
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http://dx.doi.org/10.1136/heartjnl-2018-314295DOI Listing
August 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

Visit-to-Visit Variability of Hemoglobin A in People Without Diabetes and Risk of Major Adverse Cardiovascular Events and All-Cause Mortality.

Diabetes Care 2019 01 23;42(1):134-141. Epub 2018 Oct 23.

Laboratory of Molecular Cardiology, Department of Cardiology, Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

Objective: We aimed to study whether visit-to-visit variability of glycated hemoglobin A (HbA) is associated with incident major adverse cardiovascular events (MACE), all-cause mortality, and type 2 diabetes in people without diabetes.

Research Design And Methods: We included primary care patients with no history of diabetes or cardiovascular disease and with three annual HbA measurements within normal range (<6.5% [48 mmol/mol]). For each individual, we measured the HbA variability as the SD of the residuals obtained from a linear regression on the three HbA measurements. From the linear regression, we also obtained the estimated index HbA (intercept) and the trend over time (slope). Follow-up began at the date of the third measurement. Associations between HbA variability and outcome were analyzed using Cox regression, adjusted for traditional risk factors, intercept, and trend and reported as hazard ratio per SD increase in variability (HR).

Results: In total, 6,756 individuals were included. During a median follow-up time of 6.3 years, 996 developed MACE, 856 died, and 1,267 developed type 2 diabetes. We found a significant association between increasing HbA variability and incident MACE (HR 1.09 [95% CI 1.03-1.15]) and all-cause mortality (HR 1.13 [95% CI 1.07-1.20]), whereas there were no associations with type 2 diabetes (HR 1.00 [95% CI 0.95-1.05]). We calculated 5-year absolute risks of MACE and all-cause mortality and found clinically relevant differences across several age, sex, comorbidity, and HbA variability-defined subgroups.

Conclusions: In a primary care population free of diabetes and cardiovascular disease, high HbA variability was associated with increased risks of MACE and all-cause mortality.
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http://dx.doi.org/10.2337/dc18-1396DOI Listing
January 2019

Brugada Syndrome-Associated Genetic Loci Are Associated With J-Point Elevation and an Increased Risk of Cardiac Arrest.

Front Physiol 2018 10;9:894. Epub 2018 Jul 10.

Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark.

A previous genome-wide association study found three genetic loci, rs9388451, rs10428132, and rs11708996, to increase the risk of Brugada Syndrome (BrS). Since the effect of these loci in the general population is unknown, we aimed to investigate the effect on electrocardiogram (ECG) parameters and outcomes in the general population. A cohort of 6,161 individuals (median age 45 [interquartile range (IQR) 40-50] years, 49% males), with available digital ECGs, was genotyped and subsequently followed for a median period of 13 [IQR 12.6-13.4] years. Data on outcomes were collected from Danish administrative healthcare registries. Furthermore, ~400,000 persons from UK Biobank were investigated for associations between the three loci and cardiac arrest/ventricular fibrillation (VF). Homozygote carriers of the C allele in rs6800541 intronic to had a significantly larger J-point elevation (JPE) compared with wildtype carriers (11 vs. 6 μV, < 0.001). There was an additive effect of carrying multiple BrS-associated risk alleles with an increased JPE in lead V1. None of the BrS-associated genetic loci predisposed to syncope, atrial fibrillation, or total mortality in the general Danish population. The rs9388451 genetic locus adjacent to the gene was associated with cardiac arrest/VF in an analysis using the UK Biobank study (odds ratio = 1.13 (95% confidence interval: 1.08-1.18), = 0.006). BrS-associated risk alleles increase the JPE in lead V1 in an additive manner, but was not associated with increased mortality or syncope in the general population of Denmark. However, the risk allele increased the risk of cardiac arrest/VF in the larger population study of UK Biobank indicating an important role of this common genetic locus.
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http://dx.doi.org/10.3389/fphys.2018.00894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048413PMC
July 2018

Risk Prediction of Atrial Fibrillation Based on Electrocardiographic Interatrial Block.

J Am Heart Assoc 2018 05 30;7(11). Epub 2018 May 30.

Laboratory for Molecular Cardiology, The Heart Center, Rigshospitalet University of Copenhagen, Denmark

Background: The electrocardiographic interatrial block (IAB) has been associated with atrial fibrillation (AF). We aimed to test whether IAB can improve risk prediction of AF for the individual person.

Methods And Results: Digital ECGs of 152 759 primary care patients aged 50 to 90 years were collected from 2001 to 2011. We identified individuals with P-wave ≥120 ms and the presence of none, 1, 2, or 3 biphasic P-waves in inferior leads. Data on comorbidity, medication, and outcomes were obtained from nationwide registries. We observed a dose-response relationship between the number of biphasic P-waves in inferior leads and the hazard of AF during follow-up. Discrimination of the 10-year outcome of AF, measured by time-dependent area under the curve, was increased by 1.09% (95% confidence interval 0.43-1.74%) for individuals with cardiovascular disease at baseline (CVD) and 1.01% (95% confidence interval 0.40-1.62%) for individuals without CVD, when IAB was added to a conventional risk model for AF. The highest effect of IAB on the absolute risk of AF was observed in individuals aged 60 to 70 years with CVD. In this subgroup, the 10-year risk of AF was 50% in those with advanced IAB compared with 10% in those with a normal P-wave. In general, individuals with advanced IAB and no CVD had a higher risk of AF than patients with CVD and no IAB.

Conclusions: IAB improves risk prediction of AF when added to a conventional risk model. Clinicians may consider monitoring patients with IAB more closely for the occurrence of AF, especially for high-risk subgroups.
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http://dx.doi.org/10.1161/JAHA.117.008247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015370PMC
May 2018

Analysis of 60 706 Exomes Questions the Role of De Novo Variants Previously Implicated in Cardiac Disease.

Circ Cardiovasc Genet 2017 Dec;10(6)

From the Laboratory for Molecular Cardiology, Institute for Biomedical Sciences, University of Copenhagen, Denmark (C.P.-M., G.A., J.G., J.H.S., S.H., M.S.O.); Laboratory for Molecular Cardiology, Department of Cardiology, Heart Centre at Rigshospitalet, Copenhagen University Hospital, Denmark (C.P.-M., G.A., J.G., J.H.S., S.H., M.S.O.); Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark (C.P.-M., G.A., J.G., J.H.S., S.H., M.S.O.); and Department of Clinical Medicine, University of Copenhagen, Denmark (J.H.S., S.H.).

Background: De novo variants in the exome occur at a rate of 1 per individual per generation, and because of the low reproductive fitness for de novo variants causing severe disease, the likelihood of finding these as standing variations in the general population is low. Therefore, this study sought to evaluate the pathogenicity of de novo variants previously associated with cardiac disease based on a large population-representative exome database.

Methods And Results: We performed a literature search for previous publications on de novo variants associated with severe arrhythmias and structural heart diseases and investigated whether these variants were present in the Exome Aggregation Consortium (ExAC) database (n=60 706). We identified monogenic variants in single case reports and smaller studies (≤200 subjects) and variants considered to increase susceptibility of disease in 3 larger trio studies (>1000 subjects). Of the monogenic variants, 11% (23/211) were present in ExAC, whereas 26% (802/3050) variants believed to increase susceptibility of disease were identified in ExAC. Monogenic de novo variants in ExAC had a total allele count of 109 and with ≈844 expected cases in ExAC, these variants would account for 13% of all cases in the studied diseases if truly monogenetic.

Conclusions: We observed numerous de novo variants associated with cardiac disease as standing variation in ExAC, thus these variants are less likely monogenetic causes or major risk contributors for cardiac disease. This highlights the importance of investigating the pathogenicity of de novo variants because they are not as exclusive and pathogenically evident as presumed previously.
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http://dx.doi.org/10.1161/CIRCGENETICS.117.001878DOI Listing
December 2017

Electrocardiographic Preexcitation and Risk of Cardiovascular Morbidity and Mortality: Results From the Copenhagen ECG Study.

Circ Arrhythm Electrophysiol 2017 Jun;10(6)

From the Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, Copenhagen, Denmark (M.W.S., P.V.R., J.G., M.S.O., S.H., J.H.S., A.G.H., J.B.N.); Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (S.H., L.K., J.H.S.); Department of Health Science and Technology, Aalborg University, Denmark (S.M.H., C.G., C.T.-P.); Copenhagen General Practitioners' Laboratory, Denmark (A.P.); and Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor (J.B.N.).

Background: The majority of available data on the clinical course of patients with ventricular preexcitation in the ECG originates from tertiary centers. We aimed to investigate long-term outcomes in individuals from a primary care population with electrocardiographic preexcitation.

Methods And Results: Digital ECGs from 328 638 primary care patients were collected during 2001 to 2011. We identified 310 individuals with preexcitation (age range, 8-85 years). Data on medication, comorbidity, and outcomes were collected from Danish nationwide registries. The median follow-up time was 7.4 years (quartiles, 4.6-10.3 years). Compared with the remainder of the population, patients with preexcitation had higher adjusted hazards of atrial fibrillation (hazard ratio [HR], 3.12; 95% confidence interval [CI], 2.07-4.70) and heart failure (HR, 2.11; 95% CI, 1.27-3.50). Subgroup analysis on accessory pathway location revealed a higher adjusted hazard of heart failure for a right anteroseptal accessory pathway (HR, 5.88; 95% CI, 2.63-13.1). There was no evidence of a higher hazard of death among individuals with preexcitation when looking across all age groups (HR, 1.07; 95% CI, 0.68-1.68). However, a statistically significant (=0.01) interaction analysis (<65 versus ≥65 years) indicated a higher hazard of death for patients with preexcitation ≥65 years (HR, 1.85; 95% CI, 1.07-3.18).

Conclusions: In this large ECG study, individuals with preexcitation had higher hazards of atrial fibrillation and heart failure. The higher hazard of heart failure seemed to be driven by a right anteroseptal accessory pathway. Among elderly people, we found a statistically significant association between preexcitation and a higher hazard of death.
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http://dx.doi.org/10.1161/CIRCEP.116.004778DOI Listing
June 2017

Analyses of more than 60,000 exomes questions the role of numerous genes previously associated with dilated cardiomyopathy.

Mol Genet Genomic Med 2016 Nov 17;4(6):617-623. Epub 2016 Sep 17.

Laboratory of Molecular Cardiology Department of Cardiology The Heart Centre University Hospital of Copenhagen Rigshospitalet Copenhagen Denmark.

Background: Hundreds of genetic variants have been described as disease causing in dilated cardiomyopathy (DCM). Some of these associations are now being questioned. We aimed to identify the prevalence of previously DCM associated variants in the Exome Aggregation Consortium (ExAC), in order to identify potentially false-positive DCM variants.

Methods: Variants listed as DCM disease-causing variants in the Human Gene Mutation Database were extracted from ExAC. Pathogenicity predictions for these variants were mined from dbNSFP v 2.9 database.

Results: Of the 473 DCM variants listed in HGMD, 148 (31%) were found in ExAC. The expected number of individuals with DCM in ExAC is 25 based on the prevalence in the general population. Yet, 35 variants were found in more than 25 individuals. In 13 genes, we identified all variants previously associated with DCM; four genes contained variants above our estimated cut-off. Prediction tools found ExAC variants to be significantly more tolerated when compared to variants not found in ExAC ( = 0.004).

Conclusion: In ExAC, we identified a higher genotype prevalence of variants considered disease-causing than expected. More importantly, we found 13 genes in which all variants previously associated with DCM were identified in ExAC, questioning the association of these genes with the monogenic form of DCM.
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http://dx.doi.org/10.1002/mgg3.245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118206PMC
November 2016

Numerous Brugada syndrome-associated genetic variants have no effect on J-point elevation, syncope susceptibility, malignant cardiac arrhythmia, and all-cause mortality.

Genet Med 2017 05 6;19(5):521-528. Epub 2016 Oct 6.

The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.

Purpose: We investigated whether Brugada syndrome (BrS)-associated variants identified in the general population have an effect on J-point elevation as well as whether carriers of BrS variants were more prone to experience syncope and malignant ventricular arrhythmia and had increased mortality compared with noncarriers.

Methods: All BrS-associated variants were identified using the Human Gene Mutation Database (HGMD). Individuals were randomly selected from a general population study using whole-exome sequencing data (n = 870) and genotype array data (n = 6,161) and screened for BrS-associated variants. Electrocardiograms (ECG) were analyzed electronically, and data on syncope, ventricular arrhythmias, and mortality were obtained from administrative health-care registries.

Results: In HGMD, 382 BrS-associated genetic variants were identified. Of these, 28 variants were identified in the study cohort. None of the carriers presented with type 1 BrS ECG pattern. Mean J-point elevation in V1 and V2 were within normal guideline limits for carriers and noncarriers. There was no difference in syncope susceptibility (carriers 8/624; noncarriers 98/5,562; P = 0.51), ventricular arrhythmia (carriers 4/620; noncarriers 9/5,524; P = 0.24), or overall mortality (hazard ratio 0.93, 95% CI 0.63-1.4).

Conclusions: Our data indicate that a significant number of BrS-associated variants are not the monogenic cause of BrS.Genet Med advance online publication 06 October 2016.
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http://dx.doi.org/10.1038/gim.2016.151DOI Listing
May 2017

Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval.

Eur Heart J 2015 Oct 9;36(37):2523-9. Epub 2015 Jul 9.

The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark Laboratory of Molecular Cardiology, Department of Cardiology, The Heart Centre, University Hospital of Copenhagen, Rigshospitalet, 9312, Juliane Mariesvej 20, Copenhagen OE 2100, Denmark

Aims: We studied whether variants previously associated with congenital long QT syndrome (cLQTS) have an effect on the QTc interval in a Danish population sample. Furthermore, we assessed whether carriers of variants in cLQTS-associated genes are more prone to experience syncope compared with non-carriers and whether carriers have an increased mortality compared with non-carriers.

Methods And Results: All genetic variants previously associated with cLQTS were surveyed using the Human Gene Mutation Database. We screened a Danish population-based sample with available whole-exome sequencing data (n = 870) and genotype array data (n = 6161) for putative cLQTS genetic variants. In total, 33 of 1358 variants previously reported to associate with cLQTS were identified. Of these, 10 variants were found in 8 or more individuals. Electrocardiogram results showed normal mean QTc intervals in carriers compared with non-carriers. Syncope data analysis between variant and non-variant carriers showed that 4 of 227 (1.8%) and 95 of 5861 (1.6%) individuals, respectively, had experienced syncope during follow-up (P = 0.80). There was no significant difference in overall mortality rates between carriers [7/217 (3.2%)] and non-carriers [301/6453 (4.7%)] (P = 0.24).

Conclusion: We present QTc data and register data, indicating that 26 cLQTS-associated variants neither had any effect on the QTc intervals nor on syncope propensity or overall mortality. Based on the frequency of individual gene variants, we suggest that the 10 variants frequently identified, assumed to relate to cLQTS, are less likely to associate with a dominant monogenic form of the disease.
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http://dx.doi.org/10.1093/eurheartj/ehv297DOI Listing
October 2015
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