Leucocyte telomere length and conduction system ageing.

Background: Deterioration of the cardiac conduction system is an important manifestation of cardiac ageing. Cellular ageing is accompanied by telomere shortening and telomere length (TL) is often regarded as a marker of biological ageing, potentially adding information regarding conduction disease over and above chronological age. We therefore sought to evaluate the association between leucocyte telomere length (LTL) on two related, but distinct aspects of the cardiac conduction system: ECG measures of conduction (PR interval and QRS duration) and incident pacemaker implantation in a large population-based cohort.

Prediction of Atrial and Ventricular Arrhythmias using Multiple Cardiovascular Risk Factor Polygenic Risk Scores.

Background: Atrial fibrillation (AF) prediction improves by combining clinical scores with a polygenic risk score (PRS) for AF (AF-PRS), but there are limited studies of PRS for ventricular arrhythmia (VA) prediction.

Objective: We assessed the value of including multiple PRS for cardiovascular risk factors (CV-PRS) for incident AF and VA prediction.

Methods: We used 158,733 individuals of European ancestry from UK Biobank to build three models for AF: CHARGE-AF (AF1), AF1 + AF-PRS (AF2), AF2 + CV-PRS (AF3).

Daily steps are a predictor of, but perhaps not a modifiable risk factor for Parkinson's Disease: findings from the UK Biobank.

Importance: Higher physical activity levels have been suggested as a potential modifiable risk factor for lowering the risk of incident Parkinson's disease (PD). This study uses objective measures of physical activity to investigate the role of reverse causation in the observed association.

Objective: To investigate the association between accelerometer-derived daily step count and incident PD, and to assess the impact of reverse causation on this association.

Fine mapping of candidate effector genes for heart rate.

An elevated resting heart rate (RHR) is associated with increased cardiovascular mortality. Genome-wide association studies (GWAS) have identified > 350 loci. Uniquely, in this study we applied genetic fine-mapping leveraging tissue specific chromatin segmentation and colocalization analyses to identify causal variants and candidate effector genes for RHR.

Long-term association of ultra-short heart rate variability with cardiovascular events.

Heart rate variability (HRV) is a cardiac autonomic marker with predictive value in cardiac patients. Ultra-short HRV (usHRV) can be measured at scale using standard and wearable ECGs, but its association with cardiovascular events in the general population is undetermined. We aimed to validate usHRV measured using ≤ 15-s ECGs (using RMSSD, SDSD and PHF indices) and investigate its association with atrial fibrillation, major adverse cardiac events, stroke and mortality in individuals without cardiovascular disease.

Prognostic Significance of Different Ventricular Ectopic Burdens During Submaximal Exercise in Asymptomatic UK Biobank Subjects.

Background: The consequences of exercise-induced premature ventricular contractions (PVCs) in asymptomatic individuals remain unclear. This study aimed to assess the association between PVC burdens during submaximal exercise and major adverse cardiovascular events (MI/HF/LTVA: myocardial infarction [MI], heart failure [HF], and life-threatening ventricular arrhythmia [LTVA]), and all-cause mortality. Additional end points were MI, LTVA, HF, and cardiovascular mortality.

Predicted Deleterious Variants in Cardiomyopathy Genes Prognosticate Mortality and Composite Outcomes in the UK Biobank.

Background: Inherited cardiomyopathies present with broad variation of phenotype. Data are limited regarding genetic screening strategies and outcomes associated with predicted deleterious variants in cardiomyopathy-associated genes in the general population.

Objectives: The authors aimed to determine the risk of mortality and composite cardiomyopathy-related outcomes associated with predicted deleterious variants in cardiomyopathy-associated genes in the UK Biobank.

Integration of genetic fine-mapping and multi-omics data reveals candidate effector genes for hypertension.

Genome-wide association studies of blood pressure (BP) have identified >1,000 loci, but the effector genes and biological pathways at these loci are mostly unknown. Using published association summary statistics, we conducted annotation-informed fine-mapping incorporating tissue-specific chromatin segmentation and colocalization to identify causal variants and candidate effector genes for systolic BP, diastolic BP, and pulse pressure. We observed 532 distinct signals associated with ≥2 BP traits and 84 with all three.

Premature atrial and ventricular contractions detected on wearable-format electrocardiograms and prediction of cardiovascular events.

Aims: Wearable devices are transforming the electrocardiogram (ECG) into a ubiquitous medical test. This study assesses the association between premature ventricular and atrial contractions (PVCs and PACs) detected on wearable-format ECGs (15 s single lead) and cardiovascular outcomes in individuals without cardiovascular disease (CVD).

Methods And Results: Premature atrial contractions and PVCs were identified in 15 s single-lead ECGs from = 54 016 UK Biobank participants (median age, interquartile range, age 58, 50-63 years, 54% female).

Improving explainability of deep neural network-based electrocardiogram interpretation using variational auto-encoders.

Aims: Deep neural networks (DNNs) perform excellently in interpreting electrocardiograms (ECGs), both for conventional ECG interpretation and for novel applications such as detection of reduced ejection fraction (EF). Despite these promising developments, implementation is hampered by the lack of trustworthy techniques to explain the algorithms to clinicians. Especially, currently employed heatmap-based methods have shown to be inaccurate.

Genome-Wide Analysis of Left Ventricular Maximum Wall Thickness in the UK Biobank Cohort Reveals a Shared Genetic Background With Hypertrophic Cardiomyopathy.

Background: Left ventricular maximum wall thickness (LVMWT) is an important biomarker of left ventricular hypertrophy and provides diagnostic and prognostic information in hypertrophic cardiomyopathy (HCM). Limited information is available on the genetic determinants of LVMWT.

Methods: We performed a genome-wide association study of LVMWT measured from the cardiovascular magnetic resonance examinations of 42 176 European individuals.

ECG T-Wave Morphologic Variations Predict Ventricular Arrhythmic Risk in Low- and Moderate-Risk Populations.

Background Early identification of individuals at risk of sudden cardiac death (SCD) remains a major challenge. The ECG is a simple, common test, with potential for large-scale application. We developed and tested the predictive value of a novel index quantifying T-wave morphologic variations with respect to a normal reference (TMV), which only requires one beat and a single-lead ECG.

Prediction of Coronary Artery Disease and Major Adverse Cardiovascular Events Using Clinical and Genetic Risk Scores for Cardiovascular Risk Factors.

Background: Coronary artery disease (CAD) and major adverse cardiovascular events (MACE) are the leading causes of death in the general population, but risk stratification remains suboptimal. CAD genetic risk scores (GRSs) predict risk independently from clinical tools, like QRISK3. We assessed the added value of GRSs for a variety of cardiovascular traits (CV GRSs) for predicting CAD and MACE and tested their early-life screening potential by comparing against the CAD GRS only.

Frequency, Penetrance, and Variable Expressivity of Dilated Cardiomyopathy-Associated Putative Pathogenic Gene Variants in UK Biobank Participants.

Background: There is a paucity of data regarding the phenotype of dilated cardiomyopathy (DCM) gene variants in the general population. We aimed to determine the frequency and penetrance of DCM-associated putative pathogenic gene variants in a general adult population, with a focus on the expression of clinical and subclinical phenotype, including structural, functional, and arrhythmic disease features.

Methods: UK Biobank participants who had undergone whole exome sequencing, ECG, and cardiovascular magnetic resonance imaging were selected for study.

Interleukin-1 receptor antagonist, mode of analgesia and risk of Caesarean delivery after onset of labour: a Mendelian randomisation analysis.

Background: Lower circulating levels of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra) are associated with intrapartum inflammation and epidural analgesia-related maternal fever, both of which increase the rate of obstetric interventions. We hypothesised that genetic variants determining IL-1ra levels would be associated with Caesarean delivery rates after the onset of labour.

Methods: We performed Mendelian randomisation analyses in parous women ≥16 yr old who received either non-neuraxial or neuraxial analgesia for their first two labours (UK Biobank).

Analysing electrocardiographic traits and predicting cardiac risk in UK biobank.

The electrocardiogram (ECG) is a commonly used clinical tool that reflects cardiac excitability and disease. Many parameters are can be measured and with the improvement of methodology can now be quantified in an automated fashion, with accuracy and at scale. Furthermore, these measurements can be heritable and thus genome wide association studies inform the underpinning biological mechanisms.

Direct in vivo assessment of global and regional mechanoelectric feedback in the intact human heart.

Background: Inhomogeneity of ventricular contraction is associated with sudden cardiac death, but the underlying mechanisms are unclear. Alterations in cardiac contraction impact electrophysiological parameters through mechanoelectric feedback. This has been shown to promote arrhythmias in experimental studies, but its effect in the in vivo human heart is unclear.