Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone.

Heart failure is a leading cause of morbidity and mortality. Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which act through their receptor (NPR1) to affect vasodilation, diuresis and natriuresis, lowering venous pressures and relieving venous congestion. Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect.

Rare and Common Genetic Variation Underlying Atrial Fibrillation Risk.

Importance: Atrial fibrillation (AF) has a substantial genetic component. The importance of polygenic risk is well established, while the contribution of rare variants to disease risk warrants characterization in large cohorts.

Objective: To identify rare predicted loss-of-function (pLOF) variants associated with AF and elucidate their role in risk of AF, cardiomyopathy (CM), and heart failure (HF) in combination with a polygenic risk score (PRS).

Electrocardiographic Morphology-Voltage-P-Wave-Duration (MVP) Score to Select Patients for Continuous Atrial Fibrillation Screening to Prevent Stroke.

Morphology-voltage-P-wave-duration (MVP) score combining P-wave duration (PWD), P-wave voltage in lead I (PWVI), and interatrial block (IAB) has been demonstrated to predict atrial fibrillation (AF). Therefore, this study aimed to examine MVP score and its P-wave components as potential predictors of AF screening effects on stroke prevention. This was a secondary analysis of the LOOP Study (Atrial Fibrillation detected by Continuous ECG Monitoring using Implantable Loop Recorder to prevent Stroke in High-risk Individuals) which randomized older persons (aged 70 to 90 years) with additional stroke risk factors to either continuous monitoring with implantable loop recorder and anticoagulation upon detection of AF episodes ≥6 minutes (the intervention group), or usual care.

Ventricular rate in atrial fibrillation and the risk of heart failure and death.

Aims: While clinical trials have suggested that a high ventricular rate is associated with increased risk of heart failure (HF) and mortality, all-comers studies are warranted.

Objective: To assess 1-year risk of new-onset diagnosed HF and all-cause mortality among rate-control treated patients presenting with atrial fibrillation (AF) on an electrocardiogram (ECG) according to ventricular rate.

Methods And Results: ECGs recorded at the Copenhagen General Practitioners Laboratory (2001-15) were used to identify patients with AF.

Electrocardiographic markers of subclinical atrial fibrillation detected by implantable loop recorder: insights from the LOOP Study.

Aims: Insights into subclinical atrial fibrillation (AF) development are warranted to inform the strategies of screening and subsequent clinical management upon AF detection. Hence, this study sought to characterize the onset and progression of subclinical AF with respect to 12-lead electrocardiogram (ECG) parameters.

Methods And Results: We included AF-naïve individuals aged 70-90 years with additional stroke risk factors who underwent implantable loop recorder (ILR) monitoring in the LOOP Study.

Association between primary care electrocardiogram markers and Alzheimer's disease.

Objective: The association between common electrocardiogram (ECG) markers and Alzheimer's disease has been scarcely investigated, and it is unknown if ECG markers can improve risk prediction. Thus, we aimed to examine the association between common ECG markers and Alzheimer's disease in a large population.

Methods: We studied the association between ECG markers and Alzheimer's disease using Cox models with adjustment for age, sex, and comorbidities using a large primary care population of patients aged 60 years or more.

The HUNT study: A population-based cohort for genetic research.

The Trøndelag Health Study (HUNT) is a population-based cohort of ∼229,000 individuals recruited in four waves beginning in 1984 in Trøndelag County, Norway. Approximately 88,000 of these individuals have available genetic data from array genotyping. HUNT participants were recruited during four community-based recruitment waves and provided information on health-related behaviors, self-reported diagnoses, family history of disease, and underwent physical examinations.

A fast linkage method for population GWAS cohorts with related individuals.

Linkage analysis, a class of methods for detecting co-segregation of genomic segments and traits in families, was used to map disease-causing genes for decades before genotyping arrays and dense SNP genotyping enabled genome-wide association studies in population samples. Population samples often contain related individuals, but the segregation of alleles within families is rarely used because traditional linkage methods are computationally inefficient for larger datasets. Here, we describe Population Linkage, a novel application of Haseman-Elston regression as a method of moments estimator of variance components and their standard errors.

Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants.

The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci.

Electrocardiographic P terminal force in lead V1, its components, and the association with stroke and atrial fibrillation or flutter.

Background: The electrocardiographic (ECG) marker P terminal force V1 (PTFV1) is generally perceived as a marker of left atrial pathology and has been associated with atrial fibrillation or flutter (AF).

Objective: The purpose of this study was to determine the association between PTFV1 components (duration and amplitude) and incident AF and stroke/transient ischemic attack (TIA).

Methods: The study included patients with an ECG recorded at the Copenhagen General Practitioners Laboratory in 2001 to 2011.

Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes.

Body fat distribution is a major, heritable risk factor for cardiometabolic disease, independent of overall adiposity. Using exome-sequencing in 618,375 individuals (including 160,058 non-Europeans) from the UK, Sweden and Mexico, we identify 16 genes associated with fat distribution at exome-wide significance. We show 6-fold larger effect for fat-distribution associated rare coding variants compared with fine-mapped common alleles, enrichment for genes expressed in adipose tissue and causal genes for partial lipodystrophies, and evidence of sex-dimorphism.

Germline Mutations in and Protection against Liver Disease.

Background: Exome sequencing in hundreds of thousands of persons may enable the identification of rare protein-coding genetic variants associated with protection from human diseases like liver cirrhosis, providing a strategy for the discovery of new therapeutic targets.

Methods: We performed a multistage exome sequencing and genetic association analysis to identify genes in which rare protein-coding variants were associated with liver phenotypes. We conducted in vitro experiments to further characterize associations.

Associations between primary care electrocardiography and non-Alzheimer dementia.

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.

Genome-wide meta-analysis of iron status biomarkers and the effect of iron on all-cause mortality in HUNT.

Iron is essential for many biological processes, but iron levels must be tightly regulated to avoid harmful effects of both iron deficiency and overload. Here, we perform genome-wide association studies on four iron-related biomarkers (serum iron, serum ferritin, transferrin saturation, total iron-binding capacity) in the Trøndelag Health Study (HUNT), the Michigan Genomics Initiative (MGI), and the SardiNIA study, followed by their meta-analysis with publicly available summary statistics, analyzing up to 257,953 individuals. We identify 123 genetic loci associated with iron traits.

Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension.

Background: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.

Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.

ECG and CT for the detection of left atrial enlargement in hypertensive individuals-a population-based study.

Left atrial enlargement (LAE) is associated with hypertension and an increased risk of cardiovascular morbidity and mortality. Guidelines for hypertension recommend LAE evaluation. We aimed to estimate the agreement of LAE as assessed by 12-lead electrocardiogram (ECG) and cardiac computed tomography (CT) in both the general population and hypertensive individuals.

Type 2 diabetes sex-specific effects associated with E167K coding variant in .

The rs58542926C >T (E167K) variant of the transmembrane 6 superfamily member 2 gene () is associated with increased risks for nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). Nevertheless, the role of the rs58542926 variant in glucose metabolism is poorly understood. We performed a sex-stratified analysis of the association between the rs58542926C >T variant and T2D in multiple cohorts.