Tumor necrosis factor superfamily members CD137 and OX40 ligand in vascular inflammation

Atherosclerosis, an inflammatory disease, is the major cause of cardiovascular disease - the main cause of death worldwide. T cells are central orchestrators of inflammation in atherosclerosis and critically depend on costimulation for adequate function. Hence, costimulation is pivotal for maintaining immunological homeostasis of inflammatory responses, and a dysregulated immune response may aggravate inflammation in atherosclerosis. Costimulators are therefore of central interest in the pathogenesis of cardiovascular disease. CD137 and OX40 ligand are important costimulatory molecules of the tumor necrosis factor superfamily, but their role in vascular inflammation has been unclear. We used human biobanks and clinical cohorts in combination with experimental models of atherosclerosis and atherothrombosis to investigate the involvement of CD137 and OX40 ligand in the pathogenesis of cardiovascular disease. We observed that CD137 was expressed in human and murine atherosclerosis, and that activation of CD137 promotes inflammation and atherosclerosis development in hypercholesterolemic mice. By studying gene expression in cell lines, we found an association between the single nucleotide polymorphism (SNP) rs2453021 and CD137 mRNA expression in human lymphoid cells. The minor allele of this SNP was associated with an increased intima media thickness in human carotid arteries in individuals with risk factors of cardiovascular disease. To study the influence of CD137 activation on atherothrombosis, we turned to an experimental plaque rupture model. We observed that CD137 mRNA expression was higher in ruptured compared to non-ruptured murine carotid lesions. Stimulation of CD137 promoted vascular and systemic inflammation, but did not increase plaque rupture frequency. Others have reported an association between the SNP rs3850641 in OX40 ligand and cardiovascular risk. We did observe expression of OX40 ligand on endothelial cells within human carotid atherosclerotic lesions, and the OX40 ligand expression was induced by tumor necrosis factor (TNF) in cultured vascular endothelial cells. However, we found no association with the risk for stroke in two independent populations. In conclusion, the studies in this thesis demonstrate expression of CD137 and OX40 ligand in human atherosclerotic lesions, and that activation of CD137 promotes inflammation and atherosclerosis development in hypercholesterolemic mice. These new insights on the pathophysiology of atherosclerosis warrant further studies of the therapeutic potential of interventions in costimulation for treatment of cardiovascular disease

Association of Exposure to Particular Matter and Carotid Intima-Media Thickness: A Systematic Review and Meta-Analysis

Background: Long time exposure to particular matter has been linked to myocardial infarction, stroke and blood pressure, but its association with atherosclerosis is not clear. This meta-analysis was aimed at assessing whether PM2.5 and PM10 have an effect on subclinical atherosclerosis measured by carotid intima-media thickness (CIMT). Methods: Pubmed, Ovid Medline, Embase and NICK between 1948 and 31 March 2015 were searched by combining the keywords about exposure to the outcome related words. The random-effects model was applied in computing the change of CIMT and their corresponding 95% confidence interval (95% CI). The effect of potential confounding factors was assessed by stratified analysis and the impact of traffic proximity was also estimated. Results: Among 56 identified studies, 11 articles satisfied the inclusion criteria. In overall analysis increments of 10 μg/m3 in PM2.5 and PM10 were associated with an increase of CIMT (16.79 μm; 95% CI, 4.95–28.63 μm and 4.13 μm; 95% CI, −5.79–14.04 μm, respectively). Results shown in subgroup analysis had reference value for comparing with those of the overall analysis. The impact of traffic proximity on CIMT was uncertain. Conclusions: Exposure to PM2.5 had a significant association with CIMT and for women the effect may be more obvious

Traditional Risk Factors are Causally Related to Carotid Intima-Media Thickness Progression : Inferences from Observational Cohort Studies and Interventional Trials

In the present review, associations between traditional vascular risk factors (VRFs) and carotid intima-medial thickness progression (C-IMTp) as well as the effects of therapies for VRFs control on C-IMTp were appraised to infer causality between each VRF and C-IMTp. Cohort studies indicate that smoking, binge drinking, fatness, diabetes, hypertension and hypercholesterolemia are associated with accelerated C-IMTp. An exception is physical activity, with mixed data. Interventions for the control of obesity, diabetes, hypertension and hypercholesterolemia decelerate C-IMTp. Conversely, scarce information is available regarding the effect of smoking cessation, stop of excessive alcohol intake and management of the metabolic syndrome. Altogether, these data support a causative role of several traditional VRFs on C-IMTp. Shortcomings in study design and/or ultrasonographic protocols may account for most negative studies, which underlines the importance of a careful consideration of methodological aspects in investigations using C-IMTp as the outcome

Cardiovascular risk stratification in familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is a common autosomal-dominant disorder in most European countries. Patients with FH are characterised by a raised level of low-density lipoprotein cholesterol and a high risk of premature coronary heart disease (CHD). Currently there is no consensus regarding the clinical utility to predict future coronary events or testing for the presence of subclinical atherosclerotic disease in asymptomatic patients with FH. Family screening of patients with FH as recommended by the UK National Institute of Health and Care Excellence guideline would result in finding many young individuals with a diagnosis of FH who are clinically asymptomatic. The traditional CHD risk scores, that is, the Framingham score, are insufficient in risk prediction in this group of young individuals. In addition, a better understanding of the genetic aetiology of the FH phenotype and CHD risk in monogenic FH and polygenic hypercholesterolaemia is needed. Non-invasive imaging methods such as carotid intima-media thickness measurement might produce more reliable information in finding high-risk patients with FH. The potential market authorisation of novel therapeutic agents such as PCSK9 monoclonal inhibitors makes it essential to have a better screening programme to prioritise the candidates for treatment with the most severe form of FH and at higher risk of coronary events. The utility of new imaging techniques and new cardiovascular biomarkers remains to be determined in prospective trials

Mediterranean Diet and Endothelial Function: A Review of Its Effects at Different Vascular Bed Levels

The Mediterranean diet has recently been the focus of considerable attention as a palatable model of a healthy diet. Its influence on many cardiovascular risk factors, combined with its proven effect in reducing the risk of cardiovascular events in primary prevention, has boosted scientific interest in this age-old nutritional model. Many of the underlying mechanisms behind its health-giving effects have been revealed, from the modulation of the microbiota to the function of high-density lipoproteins (HDL), and it seems to deliver its health benefits mainly by regulating several key mechanisms of atherosclerosis. In this review, we will review the evidence for its regulation of endothelial function, a key element in the early and late stages of atherosclerosis. In addition, we will assess studies which evaluate its effects on the functioning of different arterial territory vessels (mainly the microvascular, peripheral and central vascular beds), focusing mainly on the capillary, brachial and carotid arteries. Finally, we will evaluate the molecular mechanisms which may be involved

Bisphosphonates, atherosclerosis and vascular calcification: Update and systematic review of clinical studies

Background: Epidemiologic and clinical data have suggested the existence of a biologic linkage between the bone system and the vascular system. Bisphosphonates (BPs) are effective inhibitors of bone resorption and are currently considered the drugs of choice for the preven­tion and treatment of osteoporosis and related fractures. Data from several publications have suggested that BPs may also be effective in reducing the atherosclerotic process and vascular calcification, but the results of these studies are contrasting. This review aimed to allow a better understanding of the relationships between BPs and atherosclerosis in humans. Materials and methods: Electronic databases of Pubmed-Medline, Cochrane Library and SCOPUS from inception to June 30, 2016 were searched. The full texts of the articles potentially eligible were carefully assessed and reviewed. Finally, 20 studies were found to be eligible and were included in the systematic review. All included studies were published between 2000 and 2014. Results: In several studies, etidronate limited the progression of aortic and coronary calcification in hemodialysis patients, whereas the nitrogen-containing-BPs given orally did not significantly reduce vascular calcifications in patients with chronic kidney disease, kidney trasplant or in those with osteoporosis. Nitrogen-containing-BPs present favorable effects both on vessel wall thickness and on arterial elasticity due to both a reduction in serum lipids and the interaction of BPs with the bone tissue, with the consequent release of bone turnover markers and cytokines into the bloodstream. Conclusion: To sum up, the BPs seem to have the potential of influencing atherosclerosis and calcium homeostasis at the level of vascular walls with several possible mechanisms which may differ according to the type, potency, dosage and administration route of BPs. Additional studies are needed to specifically address the mechanism by which BP use could influence cardiovascular morbidity and mortality