Carotid Intima-Media Thickness and Arterial Stiffness and the Risk of Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study, Multi-Ethnic Study of Atherosclerosis (MESA), and the Rotterdam Study.

Background: We evaluated the association of carotid intima-media thickness (cIMT), carotid plaque, carotid distensibility coefficient (DC), and aortic pulse wave velocity (PWV) with incident atrial fibrillation (AF) and their role in improving AF risk prediction beyond the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)-AF risk score.

Methods And Results: We analyzed data from 3 population-based cohort studies: Atherosclerosis Risk in Communities (ARIC) Study (n=13 907); Multi-Ethnic Study of Atherosclerosis (MESA; n=6640), and the Rotterdam Study (RS; n=5220). We evaluated the association of arterial indices with incident AF and computed the C-statistic, category-based net reclassification improvement (NRI), and relative integrated discrimination improvement (IDI) of incorporating arterial indices into the CHARGE-AF risk score (age, race, height weight, systolic and diastolic blood pressure, antihypertensive medication use, smoking, diabetes, previous myocardial infarction, and previous heart failure).

Genome-wide association studies identify genetic loci for low von Willebrand factor levels.

Low von Willebrand factor (VWF) levels are associated with bleeding symptoms and are a diagnostic criterion for von Willebrand disease, the most common inherited bleeding disorder. To date, it is unclear which genetic loci are associated with reduced VWF levels. Therefore, we conducted a meta-analysis of genome-wide association studies to identify genetic loci associated with low VWF levels.

Heritabilities, proportions of heritabilities explained by GWAS findings, and implications of cross-phenotype effects on PR interval.

Electrocardiogram (ECG) measurements are a powerful tool for evaluating cardiac function and are widely used for the diagnosis and prediction of a variety of conditions, including myocardial infarction, cardiac arrhythmias, and sudden cardiac death. Recently, genome-wide association studies (GWASs) identified a large number of genes related to ECG parameter variability, specifically for the QT, QRS, and PR intervals. The aims of this study were to establish the heritability of ECG traits, including indices of left ventricular hypertrophy, and to directly assess the proportion of those heritabilities explained by GWAS variants.

No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects.

Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation.

Sex differences in lifetime risk and first manifestation of cardiovascular disease: prospective population based cohort study.

Objective: To evaluate differences in first manifestations of cardiovascular disease between men and women in a competing risks framework.

Design: Prospective population based cohort study.

Setting: People living in the community in Rotterdam, the Netherlands.

Normal values of the electrocardiogram for ages 16-90 years.

Introduction: To establish an up-to-date and comprehensive set of normal values for the clinically current measurements in the adult ECG, covering all ages for both sexes.

Methods: The study population included 13,354 individuals, taken from four population studies in The Netherlands, ranging in age from 16 to 90 years (55% men) and cardiologically healthy by commonly accepted criteria. Standard 12-lead ECGs were available for all participants.

Association of renal function with vascular stiffness in older adults: the Rotterdam study.

Background: arterial stiffening is a marker of vascular ageing and an independent risk factor for cardiovascular disease. A potential mechanism linking cardiovascular disease to chronic kidney disease might be the change in arterial elasticity. We aim to determine the association between renal function and arterial stiffness in older subjects.

FTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals.

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent.

Effects of long-term averaging of quantitative blood pressure traits on the detection of genetic associations.

Blood pressure (BP) is a heritable, quantitative trait with intraindividual variability and susceptibility to measurement error. Genetic studies of BP generally use single-visit measurements and thus cannot remove variability occurring over months or years. We leveraged the idea that averaging BP measured across time would improve phenotypic accuracy and thereby increase statistical power to detect genetic associations.

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization.

Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach.

Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17,000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established.

Arterial stiffness and hypertension in a large population of untreated individuals: the Rotterdam Study.

Objective: We studied whether arterial stiffness measured as aortic pulse wave velocity (aPWV) and carotid distensibility was associated with different subtypes of hypertension in a large population of untreated middle-aged and elderly men and women.

Methods: The study was conducted within the framework of the population-based Rotterdam Study. We included 4088 individuals with information on aPWV, with 3554 individuals with carotid distensibility measurements without use of antihypertensive medication.

Net reclassification improvement: computation, interpretation, and controversies: a literature review and clinician's guide.

The net reclassification improvement (NRI) is an increasingly popular measure for evaluating improvements in risk predictions. This article details a review of 67 publications in high-impact general clinical journals that considered the NRI. Incomplete reporting of NRI methods, incorrect calculation, and common misinterpretations were found.

Concordance for prognostic models with competing risks.

The concordance probability is a widely used measure to assess discrimination of prognostic models with binary and survival endpoints. We formally define the concordance probability for a prognostic model of the absolute risk of an event of interest in the presence of competing risks and relate it to recently proposed time-dependent area under the receiver operating characteristic curve measures. For right-censored data, we investigate inverse probability of censoring weighted (IPCW) estimates of a truncated concordance index based on a working model for the censoring distribution.

Arterial stiffness is associated with carotid intraplaque hemorrhage in the general population: the Rotterdam study.

Objective: The relation between arterial stiffness and atherosclerosis, and specifically the influence of arterial stiffness on plaque composition, is largely unknown. In a population-based study, we investigated the association between arterial stiffness and the presence and composition of carotid atherosclerotic plaques.

Approach And Results: Arterial stiffness was measured in 6527 participants (67.

Performance of Framingham cardiovascular disease (CVD) predictions in the Rotterdam Study taking into account competing risks and disentangling CVD into coronary heart disease (CHD) and stroke.

Background: To evaluate the performance of Framingham predictions of cardiovascular disease (CVD) risk corrected for the competing risk of non-CVD death, in an independent European cohort of older individuals and subsequently extend the predictions by disentangling CVD into coronary heart disease (CHD) and stroke separately.

Methods: We used the Rotterdam Study data, a prospective cohort study of individuals aged 55 years and older (N=6004), to validate the Framingham predictions of CVD, defined as first occurrence of myocardial infarction, coronary death or stroke during 15 years of follow-up, corrected for the competing risk of non-CVD death. We subsequently estimated the risks of CHD and stroke separately, and used the sum as a predictor for the total CVD risk.

Serum uric acid and chronic kidney disease: the role of hypertension.

Background: There are inconsistent findings on the role of hyperuricemia as an independent risk factor for chronic kidney disease (CKD). Hypertension has been implicated as a factor influencing the association between serum uric acid and CKD. In this population-based study we investigated the association between serum uric acid and decline in renal function and tested whether hypertension moderates this association.

Comparison of prognosis in unrecognized versus recognized myocardial infarction in men versus women >55 years of age (from the Rotterdam Study).

Unrecognized myocardial infarction (MI) is frequent in the general population. Its prognosis is reported to be at least as unpropitious as that of recognized MI, particularly in men. However, contemporary data with long follow-up are lacking.

Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals.

Serum potassium levels and the risk of atrial fibrillation: the Rotterdam Study.

Background: Atrial fibrillation is the most common sustained arrhythmia in the elderly. Serum potassium is associated with ventricular arrhythmias and cardiac arrest. Little is known about the association of serum potassium with atrial fibrillation.