Long-term health benefits and costs of measurement of carotid intima-media thickness in prevention of coronary heart disease

OBJECTIVE: Recently, it was demonstrated that information on carotid intima-media thickness (CIMT) and plaque may improve coronary heart disease (CHD) risk prediction through reclassification of some individuals to the correct risk category using the Framingham risk score. Our objective was to assess the currently unknown cost-effectiveness of CIMT measurements in primary prevention. METHODS: A hypothetical cohort of men and women aged 50-59 years and at intermediate or high CHD risk based on data from the Atherosclerosis Risk in Communities Study was simulated using a Markov model. Myocardial infarction (MI) events were used as a proxy for CHD. The effectiveness of pharmaceutical treatment was varied in the analysis. Sensitivity analysis was performed to obtain robust results. RESULTS: CIMT-based reclassification induced a 1% lower absolute risk of MI and 0.01-0.02 increase in quality-adjusted life years (QALYs) for men, and a 1-3% lower risk, and 0.03-0.05 increase in QALYs for women, over a period of 20-30 years. Corresponding costs were an additional $100 per man, and a cost-saving of$200-300 per woman. Over a 10-year period CIMT measurements were cost-effective with a probability of 66% (men), and 94% (women). Over a 30-year period, CIMT measurements had acceptable cost-effectiveness for men and women. CONCLUSION: Performing CIMT measurements in asymptomatic men and women aged 50-59 years results in additional, but small, health benefits. It takes time for these health benefits to outweigh the initial CIMT measurement costs. Our results support CIMT measurements for cardiovascular risk stratification, in particular for women, when focusing on long-term health

Discovering Distinct Phenotypical Clusters in Heart Failure Across the Ejection Fraction Spectrum:a Systematic Review

Review Purpose: This systematic review aims to summarise clustering studies in heart failure (HF) and guide future clinical trial design and implementation in routine clinical practice. Findings: 34 studies were identified (n = 19 in HF with preserved ejection fraction (HFpEF)). There was significant heterogeneity invariables and techniques used. However, 149/165 described clusters could be assigned to one of nine phenotypes: 1) young, low comorbidity burden; 2) metabolic; 3) cardio-renal; 4) atrial fibrillation (AF); 5) elderly female AF; 6) hypertensive-comorbidity; 7) ischaemic-male; 8) valvular disease; and 9) devices. There was room for improvement on important methodological topics for all clustering studies such as external validation and transparency of the modelling process.Summary:The large overlap between the phenotypes of the clustering studies shows that clustering is a robust approach for discovering clinically distinct phenotypes. However, future studies should invest in a phenotype model that can be implemented in routine clinical practice and future clinical trial design. Graphical Abstract: HF = heart failure, EF = ejection fraction, HFpEF = heart failure with preserved ejection fraction, HFrEF = heart failure with reduced ejection fraction, CKD = chronic kidney disease, AF = atrial fibrillation, IHD = ischaemic heart disease, CAD = coronary artery disease, ICD = implantable cardioverter-defibrillator, CRT = cardiac resynchronization therapy, NT-proBNP = N-terminal pro b-type natriuretic peptide, BMI = Body Mass Index, COPD = Chronic obstructive pulmonary disease. [Figure not available: see fulltext.]</p

Heart disease in the Netherlands: A quantitative update

In this review we discuss cardiovascular mortality, incidence and prevalence of heart disease, and cardiac interventions and surgery in the Netherlands. We combined most recently available data from various Dutch cardiovascular registries, Dutch Hospital Data (LMR), Statistics Netherlands (CBS), and population-based cohort studies, to provide a broad quantitative update. The absolute number of people dying from cardiovascular diseases is declining and cardiovascular conditions are no longer the leading cause of death in the Netherlands. However, a substantial burden of morbidity persists with 400,000 hospitalisations for cardiovascular disease involving over 80,000 cardiac interventions annually. In the Netherlands alone, an estimated 730,000 persons are currently diagnosed with coronary heart disease, 120,000 with heart failure, and 260,000 with atrial fibrillation. These numbers emphasise the continuous need for dedicated research on prevention, diagnosis, and treatment of heart disease in our country

Critical temperature of an anisotropic superconductor containing both nonmagnetic and magnetic impurities

The combined effect of both nonmagnetic and magnetic impurities on the superconducting transition temperature is studied theoretically within the BCS model. An expression for the critical temperature as a function of potential and spin-flip scattering rates is derived for a two-dimensional superconductor with arbitrary in-plane anisotropy of the superconducting order parameter, ranging from isotropic s-wave to d-wave (or any pairing state with nonzero angular momentum) and including anisotropic s-wave and mixed (d+s)-wave as particular cases. This expression generalizes the well-known Abrikosov-Gor'kov formula for the critical temperature of impure superconductors. The effect of defects and impurities in high temperature superconductors is discussed.Comment: 4 eps figure

Exome-chip association analysis of intracranial aneurysms

Objective: To investigate to what extent low-frequency genetic variants (with minor allele frequencies <5%) affect the risk of intracranial aneurysms (IAs). Methods: One thousand fifty-six patients with IA and 2,097 population-based controls from the Netherlands were genotyped with the Illumina HumanExome BeadChip. After quality control (QC) of samples and single nucleotide variants (SNVs), we conducted a single variant analysis using the Fisher exact test. We also performed the variable threshold (VT) test and the sequence kernel association test (SKAT) at different minor allele count (MAC) thresholds of >5 and >0 to test the hypothesis that multiple variants within the same gene are associated with IA risk. Significant results were tested in a replication cohort of 425 patients with IA and 311 controls, and results of the 2 cohorts were combined in a meta-analysis. Results: After QC, 995 patients with IA and 2,080 controls remained for further analysis. The single variant analysis comprising 46,534 SNVs did not identify significant loci at the genome-wide level. The gene-based tests showed a statistically significant association for fibulin 2 (FBLN2) (best p = 1 × 10-6 for the VT test, MAC >5). Associations were not statistically significant in the independent but smaller replication cohort (p > 0.57) but became slightly stronger in a meta-analysis of the 2 cohorts (best p = 4.8 × 10-7 for the SKAT, MAC ≥1). Conclusion: Gene-based tests indicated an association for FBLN2, a gene encoding an extracellular matrix protein implicated in vascular wall remodeling, but independent validation in larger cohorts is warranted. We did not identify any significant associations for single low-frequency genetic variants

Psychosocial factors and cancer incidence (PSY-CA):Protocol for individual participant data meta-analyses

OBJECTIVES: Psychosocial factors have been hypothesized to increase the risk of cancer. This study aims (1) to test whether psychosocial factors (depression, anxiety, recent loss events, subjective social support, relationship status, general distress, and neuroticism) are associated with the incidence of any cancer (any, breast, lung, prostate, colorectal, smoking-related, and alcohol-related); (2) to test the interaction between psychosocial factors and factors related to cancer risk (smoking, alcohol use, weight, physical activity, sedentary behavior, sleep, age, sex, education, hormone replacement therapy, and menopausal status) with regard to the incidence of cancer; and (3) to test the mediating role of health behaviors (smoking, alcohol use, weight, physical activity, sedentary behavior, and sleep) in the relationship between psychosocial factors and the incidence of cancer.METHODS: The psychosocial factors and cancer incidence (PSY-CA) consortium was established involving experts in the field of (psycho-)oncology, methodology, and epidemiology. Using data collected in 18 cohorts (N = 617,355), a preplanned two-stage individual participant data (IPD) meta-analysis is proposed. Standardized analyses will be conducted on harmonized datasets for each cohort (stage 1), and meta-analyses will be performed on the risk estimates (stage 2).CONCLUSION: PSY-CA aims to elucidate the relationship between psychosocial factors and cancer risk by addressing several shortcomings of prior meta-analyses.</p

Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.

BACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.BH

Discovery of novel heart rate-associated loci using the Exome Chip

Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses. Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods. We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants. Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies