The definition of low wall shear stress and its effect on plaque progression estimation in human coronary arteries

Wall shear stress (WSS), the frictional force of the blood on the vessel wall, plays a crucial role in atherosclerotic plaque development. Low WSS has been associated with plaque growth, however previous research used different approaches to define low WSS to investigate its effect on plaque progression. In this study, we used four methodologies to allocate low, mid and high WSS in one dataset of human coronary arteries and investigated the predictive power of low WSS for plaque progression. Coronary reconstructions were based on multimodality imaging, using intravascular ultrasound and CT-imaging. Vessel-specific flow was measured using Doppler wire and computational fluid dynamics was performed to calculate WSS. The absolute WSS range varied greatly between the coronary arteries. On the population level, the established pattern of most plaque progression at low WSS was apparent in all methodologies defining the WSS categories. However, for the individual patient, when using measured flow to determine WSS, the absolute WSS values range so widely, that the use of absolute thresholds to determine low WSS was not appropriate to identify regions at high risk for plaque progression

Physiology and coronary artery disease: emerging insights from computed tomography imaging based computational modeling

Improvements in spatial and temporal resolution now permit robust high quality characterization of presence, morphology and composition of coronary atherosclerosis in computed tomography (CT). These characteristics include high risk features such as large plaque volume, low CT attenuation, napkin-ring sign, spotty calcification and positive remodeling. Because of the high image quality, principles of patient-specific computational fluid dynamics modeling of blood flow through the coronary arteries can now be applied to CT and allow the calculation of local lesion-specific hemodynamics such as endothelial shear stress, fractional flow reserve and axial plaque stress. This review examines recent advances in coronary CT image-based computational modeling and discusses the opportunity to identify lesions at risk for rupture much earlier than today through the combination of anatomic and hemodynamic information

Design of the Quality of Life in Motion (QLIM) study: a randomized controlled trial to evaluate the effectiveness and cost-effectiveness of a combined physical exercise and psychosocial training program to improve physical fitness in children with cancer

<p>Abstract</p> <p>Background</p> <p>Childhood cancer and its treatment have considerable impact on a child's physical and mental wellbeing. Especially long-term administration of chemotherapy and/or radiotherapy impairs physical fitness both during and after therapy, when children often present with muscle weakness and/or low cardiorespiratory fitness. Physical exercise can improve these two elements of physical fitness, but the positive effects of physical exercise might be further increased when a child's wellbeing is simultaneously enhanced by psychosocial training. Feeling better may increase the willingness and motivation to engage in sports activities. Therefore, this multi-centre study evaluates the short and long-term changes in physical fitness of a child with a childhood malignancy, using a combined physical exercise and psychosocial intervention program, implemented during or shortly after treatment. Also examined is whether positive effects on physical fitness reduce inactivity-related adverse health problems, improve quality of life, and are cost-effective.</p> <p>Methods</p> <p>This multi-centre randomized controlled trial compares a combined physical and psychosocial intervention program for children with cancer, with care as usual (controls). Children with cancer (aged 8-18 years) treated with chemotherapy and/or radiotherapy, and who are no longer than 1 year post-treatment, are eligible for participation. A total of 100 children are being recruited from the paediatric oncology/haematology departments of three Dutch university medical centres. Patients are stratified according to pubertal stage (girls: age ≤10 or >10 years; boys: ≤11 or >11 years), type of malignancy (haematological or solid tumour), and moment of inclusion into the study (during or after treatment), and are randomly assigned to the intervention or control group.</p> <p>Discussion</p> <p>Childhood cancer patients undergoing long-term cancer therapy may benefit from a combined physical exercise and psychosocial intervention program since it may maintain or enhance their physical fitness and increase their quality of life. However, the feasibility, patient need, and effectiveness of such a program should be established before the program can be implemented as part of standard care.</p> <p>Trial registration number</p> <p>NTR1531 (The Netherlands National Trial Register)</p

Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.Peer reviewe

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

The trans-ancestral genomic architecture of glycemic traits

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution. A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.Peer reviewe

Wall shear stress topological skeleton variability predicts plaque growth in human coronary arteries

Introduction In last decades wall shear stress (WSS) has gained consensus as hemodynamic mechanism for coronary atherosclerosis. However, the exact biomechanical stimulus affecting early atherosclerosis is still undetermined. To bridge this knowledge gap, the WSS topological skeleton (TS) is receiving increasing interest, because of its link with flow disturbances associated to vascular dysfunction, and its capability to improve the description of the complex biomechanical stimulus affecting atherosclerosis evolution. The WSS TS consists of fixed points, where WSS vanishes, and unstable/stable manifolds, where WSS exerts a contraction/expansion action on the endothelium, thus dictating intracellular and cell-cell tension definition. Here we test the ability of WSS TS to predict the coronary artery plaque burden (PB) temporal evolution in 49 patient-specific computational models of human coronary arteries. Methods The methods workflow is provided in Figure 1. Forty-eight hemodynamically stable patients with acute coronary syndrome and at least one non-culprit coronary segment, were enrolled5. Previous coronary bypass graft surgery, renal insufficiency (creatinine clearing<50ml/min), ejection fraction<30%, and atrial fibrillation, were considered as exclusion criteria. After successful percutaneous coronary intervention of culprit vessel, the non-culprit coronary segment was imaged by coronary computed tomography (CCTA) angiography and intravascular ultrasound (IVUS) at intervention time (T1) and at 1 year follow-up (T2). 3D vessel geometries were reconstructed at T1, and computational fluid dynamics simulations were performed prescribing patient-specific boundary conditions. WSS analysis was based on time average WSS (TAWSS), and topological shear variation index (TSVI),2 quantifying the variability of the local WSS contraction/expansion action on the endothelium along the cardiac cycle. PB growth was measured on IVUS images as the difference between PB (100*plaque area/total vessel area) at T2 and T1, adjusted to PB at T1 and averaged over 1.5mm/45° luminal sectors. WSS-based quantities were averaged over the same luminal sectors and classified into artery-specific (low, mid, and high) tertiles. Results Figure 2 presents the luminal distributions of T2-T1 PB growth, and TAWSS and TSVI at T1 for six explanatory cases. The luminal sectors-based distribution of adjusted PB growth within low, mid, or high values of TAWSS and TSVI is also reported. Luminal sectors exposed to high TSVI at T1 exhibit T2-T1 PB growth significantly higher than sectors exposed to low (p<0.05) or mid (p<0.01) TSVI. A clear trend (even if not significant) emerges also for the exposure to low TAWSS at T1 and PB growth, the latter being higher in luminal sectors where TAWSS is low and vice versa. Conclusion Overall, the findings of this study support the hypothesis that WSS is involved in human coronary atherosclerosis development at early stage. In detail, it emerges that luminal exposure to high TSVI is associated with PB growth, a hallmark of early atherosclerosis. A clear inverse trend emerges between PB growth and TAWSS. Physically, TSVI quantifies the variability of WSS contraction/expansion action on the endothelium, describing a different hemodynamic stimulus with respect to low TAWSS. This study confirms recent findings on TSVI as biomechanical marker of vascular disease, encouraging further clinical trials for a clinical translation of this concept