Atherothrombosis and Oxidative Stress: Mechanisms and Management in Elderly

Significance: The incidence of cardiovascular events (CVEs) increases with age, representing the main cause of death in an elderly population. Aging is associated with overproduction of reactive oxygen species (ROS), which may affect clotting and platelet activation, and impair endothelial function, thus predisposing elderly patients to thrombotic complications. Recent Advances: There is increasing evidence to suggest that aging is associated with an imbalance between oxidative stress and antioxidant status. Thus, upregulation of ROS-producing enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and myeloperoxidase, along with downregulation of antioxidant enzymes, such as superoxide dismutase and glutathione peroxidase, occurs during aging. This imbalance may predispose to thrombosis by enhancing platelet and clotting activation and eliciting endothelial dysfunction. Recently, gut-derived products, such as trimethylamine N-oxide (TMAO) and lipopolysaccharide, are emerging as novel atherosclerotic risk factors, and gut microbiota composition has been shown to change by aging, and may concur with the increased cardiovascular risk in the elderly. Critical Issues: Antioxidant treatment is ineffective in patients at risk or with cardiovascular disease. Further, anti-thrombotic treatment seems to work less in the elderly population. Future Directions: Interventional trials with antioxidants targeting enzymes implicated in aging-related atherothrombosis are warranted to explore whether modulation of redox status is effective in lowering CVEs in the elderly

Meta-analysis of genes in commercially available nutrigenomic tests denotes lack of association with dietary intake and nutrient-related pathologies

Nutrigenomics is an emerging discipline that aims to investigate how individual genetic composition correlates with dietary intake, as well as how nutrition influences gene expression. Herein, the fundamental question relates to the value of nutrigenomics testing on the basis of the currently available scientific evidence. A thorough literature search has been conducted in PubMed scientific literature database for nutrigenomics research studies on 38 genes included in nutrigenomics tests provided by various private genetic testing laboratories. Data were subsequently meta-analyzed to identify possible associations between the genes of interest and dietary intake and/or nutrient-related pathologies. Data analysis occurred according to four different models due to data sparsity and inconsistency. Data from 524,592 individuals (361,153 cases and 163,439 controls) in a total of 1,170 entries were obtained. Conflicting findings indicated that there was a great incompatibility regarding the associations (or their absence) identified. No specific-and statistically significant-association was identified for any of the 38 genes of interest. In those cases, where a weak association was demonstrated, evidence was based on a limited number of studies. As solid scientific evidence is currently lacking, commercially available nutrigenomics tests cannot be presently recommended. Notwithstanding, the need for a thorough and continuous nutrigenomics research is evident as it is a highly promising tool towards precision medicine

Paraoxonase gene polymorphisms and haplotype analysis in a stroke population

Peer reviewedPublisher PD

Depletion of B-cells with rituximab improves endothelial function and reduces inflammation among individuals with rheumatoid arthritis.

BackgroundIndividuals with rheumatoid arthritis (RA) are at increased risk for cardiovascular disease, partly due to systemic inflammation and endothelial dysfunction. B-cells play an important pathogenic role in the inflammatory process that drives RA disease activity. Rituximab, a chimeric murine/human monoclonal antibody that depletes B-cells, is an effective therapy for RA. The purpose of this study was to determine whether B-cell depletion with rituximab reduces systemic inflammation and improves macrovascular (brachial artery flow-mediated dilation, FMD) and microvascular (reactive hyperemia) endothelial function in RA patients.Methods and resultsRA patients received a single course of rituximab (1000 mg IV infusion at baseline and on day 15). FMD, reactive hyperemia, inflammatory markers, and clinical assessments were performed at baseline, week 12, and week 24. Twenty patients (95% female, median age 54 years) completed the study. Following treatment, FMD improved from a baseline of 4.5±0.4% to 6.4±0.6% at 12 weeks (mean±SE; P<0.0001), followed by a decline at week 24; a similar pattern was observed for hyperemic velocity. Significant decreases in RA disease scores, high-sensitivity C-reactive protein, erythrocyte sedimentation rate, and circulating CD19+ B-cells were sustained through week 24. Cholesterol and triglycerides became significantly although modestly elevated during the study.ConclusionsDepletion of B-cells with rituximab improved macrovascular and microvascular endothelial function and reduced systemic inflammation, despite modest elevation in lipids. Given these results, rituximab should be evaluated in the future for its possible role in reducing excess cardiovascular risk in RA.Clinical trial registrationURL http://ClinicalTrials.gov. Unique identifier: NCT00844714

High plasma leptin levels confer increased risk of atherosclerosis in women with systemic lupus erythematosus, and are associated with inflammatory oxidised lipids.

BackgroundPatients with systemic lupus erythematosus (SLE) are at increased risk of atherosclerosis, even after accounting for traditional risk factors. High levels of leptin and low levels of adiponectin are associated with both atherosclerosis and immunomodulatory functions in the general population.ObjectiveTo examine the association between these adipokines and subclinical atherosclerosis in SLE, and also with other known inflammatory biomarkers of atherosclerosis.MethodsCarotid ultrasonography was performed in 250 women with SLE and 122 controls. Plasma leptin and adiponectin levels were measured. Lipoprotein a (Lp(a)), oxidised phospholipids on apoB100 (OxPL/apoB100), paraoxonase, apoA-1 and inflammatory high-density lipoprotein (HDL) function were also assessed.ResultsLeptin levels were significantly higher in patients with SLE than in controls (23.7±28.0 vs 13.3±12.9 ng/ml, p<0.001). Leptin was also higher in the 43 patients with SLE with plaque than without plaque (36.4±32.3 vs 20.9±26.4 ng/ml, p=0.002). After multivariate analysis, the only significant factors associated with plaque in SLE were leptin levels in the highest quartile (≥29.5 ng/ml) (OR=2.8, p=0.03), proinflammatory HDL (piHDL) (OR=12.8, p<0.001), age (OR=1.1, p<0.001), tobacco use (OR=7.7, p=0.03) and hypertension (OR=3.0, p=0.01). Adiponectin levels were not significantly associated with plaque in our cohort. A significant correlation between leptin and piHDL function (p<0.001), Lp(a) (p=0.01) and OxPL/apoB100 (p=0.02) was also present.ConclusionsHigh leptin levels greatly increase the risk of subclinical atherosclerosis in SLE, and are also associated with an increase in inflammatory biomarkers of atherosclerosis such as piHDL, Lp(a) and OxPL/apoB100. High leptin levels may help to identify patients with SLE at risk of atherosclerosis

Apolipoprotein E related Co-Morbidities and Alzheimer’s disease

The primary goal of advancement in clinical services is to provide a health care system that enhances an individual’s quality of life. Incidence of diabetes mellitus, cardiovascular disease and associated dementia coupled with the advancing age of the population, have led to an increase in the worldwide challenge to the healthcare system. In order to overcome these challenges prior knowledge of common, reliable risk factors and their effectors is essential. The oral health constitutes one such relatively unexplored but indispensable risk factor for aforementioned co-morbidities, in the form of poor oral hygiene and tooth loss during aging. Behavioural traits such as low education, smoking, poor diet, neglect of oral health, lack of exercise, and hypertension are few of the risk factors that are shared commonly amongst these conditions. In addition, common genetic susceptibility traits such as the apolipoprotein ɛ gene, together with an individual’s life style can also influence the development of co-morbidities such as periodontitis, atherosclerosis/stroke, diabetes, and Alzheimer’s disease. This review specifically addresses the susceptibility of apolipoprotein ε gene allele 4 as the plausible commonality for the etiology of co-morbidities that eventually result from periodontal diseases and ultimately progress to dementia

Leukocyte recruitment in atherosclerosis: Potential targets for therapeutic approaches?

Abstract.: Atherosclerosis is a complex inflammatory disease involving cellular migration and interaction. Vascular injury in response to different cardiovascular risk factors enhances endothelial dysfunction, which in turn promotes the expression of inflammatory markers and transendothelial leukocyte migration. Recruitment of leukocytes from the blood stream into the vessel intima is a crucial step for the development of the disease. Recent findings have highlighted the role of chemokines, chemokine receptors, adhesion molecules, and gap junctions in this process by acting as chemoattractant, adhesive, or intercellular communication molecules. In this short review, we summarize new data concerning the different steps from leukocyte arrest to transendothelial migration and discuss potential new therapeutic approaches concerning these processe

Association between apolipoprotein E genotype and carotid intima-media thickness may suggest a specific effect on large artery atherothrombotic stroke

BACKGROUND AND PURPOSE: Apolipoprotein E genotype (APOE) influences cholesterol levels and ischemic heart disease. Although there is no convincing overall association with ischemic stroke, APOE may influence large artery (atherothrombotic) stroke, for which carotid intima-media thickness (CIMT) is an informative intermediate phenotype. We therefore performed a systematic review and meta-analysis of the association between APOE and CIMT. METHODS: We sought all published studies assessing the association between APOE and CIMT. From each study, we extracted available data on study methods, subjects’ characteristics, and mean (and standard deviation) CIMT for each genotype or genotype group. We calculated study-specific and random effects pooled differences in mean CIMT between genotype groups, and assessed heterogeneity between studies and predefined subgroups using I(2) and χ(2) statistics. RESULTS: Meta-analysis of 22 published studies (30 879 subjects) showed a significant association between APOE and CIMT (pooled mean difference ε4-versus ε2-allele containing genotypes 46 μm, 95% CI 29 to 62, P<0.00001). We found evidence of small study (mainly publication) bias, with a diminished (but still highly statistically significant) association in studies of >1000 subjects (pooled mean difference 17 μm, 95% CI 12 to 23, P<0.00001). The association was larger among high vascular risk and eastern Asian populations, but this may simply reflect the smaller size of these studies. CONCLUSION: Our results show a clear association of APOE with CIMT, even though publication bias means that this is overestimated by the published literature. These findings suggest the possibility of a specific association with large artery ischemic stroke

Vascular consequences of menopause and hormone therapy: Importance of timing of treatment and type of estrogen

Premenopausal women have a lower risk for cardiovascular events, and mortality due to coronary vascular disease (CVD) in premenopausal women is rare. These facts suggest that endogenous estrogens, such as estradiol, protect the cardiovascular system, and several observational studies and a few small clinical studies conducted in healthy and younger postmenopausal women support this hypothesis. In contrast, two large randomized clinical trials (RCTs), using conjugated equine estrogens and conducted in older women with established CVD or without overt CVD, failed to demonstrate protection against CVD by exogenous estrogens. These divergent findings have resulted in confusion with regard to the association between estrogen deficiency and CVD in postmenopausal women. In order to reconcile these contradictory findings, it is necessary to examine the pathophysiology associated with age-dependent changes within the vessel wall and to compare the pharmacology of different types of estrogens. Understanding age-dependent changes in vascular pathology and the pharmacology of different estrogens may facilitate the development of therapeutic strategies for hormone replacement therapy (HRT) that would be effective in delaying vascular remodeling leading to CVD following menopause. In this review we provide an overview of the impact of menopause and estrogen deficiency on vascular remodeling and emphasize the importance of timing and type of estrogen to achieve maximum benefits with regard to reducing the risk of CV