Lipoprotein(a) is associated with a larger systemic burden of arterial calcification

AIMS: Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for cardiovascular disease. However, population-based evidence on the link between Lp(a) and subclinical arteriosclerosis is lacking. We assessed associations of Lp(a) concentrations with arteriosclerosis in multiple arteries. METHODS AND RESULTS: From the population-based Rotterdam study, 2354 participants (mean age: 69.5 years, 52.3% women) underwent non-contrast computed tomography to assess arterial calcification as a hallmark of arteriosclerosis. We quantified the volume of coronary artery calcification (CAC), aortic arch calcification (AAC), extracranial (ECAC), and intracranial carotid artery calcification (ICAC). All participants underwent blood sampling, from which plasma Lp(a) concentrations were derived. The association of plasma Lp(a) levels was assessed with calcification volumes and with severe calcification (upper quartile of calcification volume) using sex-stratified multivariable linear and logistic regression models. Higher Lp(a) levels were associated with larger ln-transformed volumes of CAC [fully adjusted beta 95% confidence interval (CI) per 1 standard deviation (SD) in women: 0.09, 95% CI 0.04-0.14, men: 0.09, 95% CI 0.03-0.14], AAC (women: 0.06, 95% CI 0.01-0.11, men: 0.09, 95% CI 0.03-0.14), ECAC (women: 0.07, 95% CI 0.02-0.13, men: 0.08, 95% CI 0.03-0.14), and ICAC (women: 0.09, 95% CI 0.03-0.14, men: 0.05, 95% CI -0.02 to 0.11]. In the highest Lp(a) percentile, severe ICAC was most prevalent in women [fully adjusted odds ratio (OR) 2.41, 95% CI 1.25-4.63] and severe AAC in men (fully adjusted OR 3.29, 95% CI 1.67-6.49). CONCLUSION: Higher Lp(a) was consistently associated with a larger calcification burden in all major arteries. The findings of this study indicate that Lp(a) is a systemic risk factor for arteriosclerosis and thus potentially an effective target for treatment. Lp(a)-reducing therapies may reduce the burden from arteriosclerotic events throughout the arterial system. TRANSLATIONAL PERSPECTIVE: In 2354 participants from the Rotterdam study, we assessed the link between Lp(a) concentrations and arterial calcifications, as proxy for arteriosclerosis, in major arteries. We found that higher Lp(a) levels were consistently associated with larger volumes of calcification in the coronary arteries, aortic arch, extracranial carotid arteries, and intracranial carotid arteries. The findings of our study indicate that Lp(a) is a systemic risk factor for arteriosclerosis, suggesting that the systemic burden of arteriosclerosis throughout the arterial system could be reduced by targeting Lp(a).</p

Theoretical approach to predict transverse impact response of variable-stiffness curved composite plates

This research studies the low velocity impact behaviour of variable stiffness curved composite plates. Since variable thickness within composite structures is recognised as an important factor on the performance of the structures, significant mathematical modelling to predict the impact response of these types of structure is essential. Varying thicknesses of sections is widely found in aerospace and automotive composite sub structures. It has been observed that changing of geometry of these sections can vary the dynamic response of anisotropic composite structures under a range of monolithic and dynamic loading conditions. Here we have used first order shear deformation theory to predict the contact force history of curved composite plates and the same approach was used for variable thickness composite plates, which provides the main novelty of this research. It was shown that the model developed here is capable of successfully predicting the response of variable stiffness composite plates with a range of layups and geometry designs under impact loading conditions

Serum insulin levels are associated with vulnerable plaque components in the carotid artery: the Rotterdam Study

Background: To investigate the association between fasting serum insulin and glucose levels with atherosclerotic plaque composition in the carotid artery. Impaired insulin and glucose levels are implicated in the etiology of cardiovascular disease; however, their influence on the formation and composition of atherosclerotic plaqu

Smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic traits

Background: Tobacco smoking is a well-known modifiable risk factor for many chronic diseases, including cardiovascular disease (CVD). One of the proposed underlying mechanism linking smoking to disease is via epigenetic modifications, which could affect the expression of disease-associated genes. Here, we conducted a three-way association study to identify the relationship between smoking-related changes in DNA methylation and gene expression and their associations with cardio-metabolic traits. Results We selected 2549 CpG sites and 443 gene expression probes associated with current versus never smokers, from the largest epigenome-wide association study and transcriptome-wide association study to date. We examined three-way associations, including CpG versus gene expression, cardio-metabolic trait versus CpG, and cardio-metabolic trait versus gene expression, in the Rotterdam study. Subsequently, we replicated our findings in The Cooperative Health Research in the Region of Augsburg (KORA) study. After correction for multiple testing, we identified both cis- and trans-expression quantitative trait methylation (eQTM) associations in blood. Specifically, we found 1224 smoking-related CpGs associated with at least one of the 443 gene expression probes, and 200 smoking-related gene expression probes to be associated with at least one of the 2549 CpGs. Out of these, 109 CpGs and 27 genes were associated with at least one cardio-metabolic trait in the Rotterdam Study. We were able to replicate the associations with cardio-metabolic traits of 26 CpGs and 19 genes in the KORA study. Furthermore, we identified a three-way association of triglycerides with two CpGs and two genes (GZMA;CLDND1), and BMI with six CpGs and two genes (PID1;LRRN3). Finally, our results revealed the mediation effect of cg03636183 (F2RL3), cg06096336 (PSMD1), cg13708645 (KDM2B), and cg17287155 (AHRR) within the association between smoking and LRRN3 expression. Conclusions: Our study indicates that smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic risk factors. These findings may provide additional insights into the molecular mechanisms linking smoking to the development of CVD

Natriuretic peptides and integrated risk assessment for cardiovascular disease. an individual-participant-data meta-analysis

BACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment. METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure. FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure. INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention

Accelerated menopausal changes as human disease model 'FOCUM' for the development of osteoarthritis and other degenerative disorders:protocol for a prospective cohort study

INTRODUCTION: The incidence of degenerative disorders, including osteoarthritis (OA), increases rapidly in women after menopause. However, the influence of the menopause is still insufficiently investigated due to the slowness of menopausal transition. In this study, a novel human model is used in which it is expected that menopausal-related changes will occur faster. This is the Females discontinuing Oral Contraceptives Use at Menopausal age model. The ultimate aim is to link these changes to OA and other degenerative disorders, including cardiovascular diseases, diabetes, osteoporosis and tendinopathies. METHODS AND ANALYSIS: This is a pilot observational prospective cohort study with 2 years of follow-up. Fifty women aged 50–60 who use oral contraceptive (OC) and have the intention to stop are included. Measurements are performed once before stopping OC, and four times thereafter at 6 weeks, 6 months, 1 year and 2 years. At every time point, a questionnaire is filled in and a sample of blood is drawn. At the first and final time points, a physical examination, hand radiographs and a MRI scan of one knee are performed. The primary OA outcome is progression of the MRI Osteoarthritis Knee Score. Secondary OA outcomes are the development of clinical knee and hand OA, development of knee OA according to the MRI definition, and progression of radiographic features for hand OA. Principal component analysis will be used to assess which changes occur after stopping OC. Univariate and multivariate generalised estimating equation models will be used to test for associations between these components and OA. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee of the Erasmus MC University Medical Center Rotterdam (MEC-2019-0592). All participants must give informed consent before data collection. Results will be disseminated in national and international journals. TRIAL REGISTRATION NUMBER: NL70796.078.19

Multi-Omics Analysis Reveals MicroRNAs Associated With Cardiometabolic Traits

MicroRNAs (miRNAs) are non-coding RNA molecules that regulate gene expression. Extensive research has explored the role of miRNAs in the risk for type 2 diabetes (T2D) and