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

Drug treatment of hypertension: focus on vascular health

Hypertension, the most common preventable risk factor for cardiovascular disease and death, is a growing health burden. Serious cardiovascular complications result from target organ damage including cerebrovascular disease, heart failure, ischaemic heart disease and renal failure. While many systems contribute to blood pressure (BP) elevation, the vascular system is particularly important because vascular dysfunction is a cause and consequence of hypertension. Hypertension is characterised by a vascular phenotype of endothelial dysfunction, arterial remodelling, vascular inflammation and increased stiffness. Antihypertensive drugs that influence vascular changes associated with high BP have greater efficacy for reducing cardiovascular risk than drugs that reduce BP, but have little or no effect on the adverse vascular phenotype. Angiotensin converting enzyme ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) improve endothelial function and prevent vascular remodelling. Calcium channel blockers also improve endothelial function, although to a lesser extent than ACEIs and ARBs. Mineralocorticoid receptor blockers improve endothelial function and reduce arterial stiffness, and have recently become more established as antihypertensive drugs. Lifestyle factors are essential in preventing the adverse vascular changes associated with high BP and reducing associated cardiovascular risk. Clinicians and scientists should incorporate these factors into treatment decisions for patients with high BP, as well as in the development of new antihypertensive drugs that promote vascular health

Effects of vitamin D supplementation on endothelial function:a systematic review and meta-analysis of randomised clinical trials

Background: In addition to regulating calcium homoeostasis and bone health, vitamin D influences vascular and metabolic processes including endothelial function (EF) and insulin signalling. This systematic review and meta-analysis of randomised clinical trials (RCTs) were conducted to investigate the effect of vitamin D supplementation on EF and to examine whether the effect size was modified by health status, study duration, dose, route of vitamin D administration, vitamin D status (baseline and post-intervention), body mass index (BMI), age and type of vitamin D.  Methods: We searched the Medline, Embase, Cochrane Library and Scopus databases from inception until March 2015 for studies meeting the following criteria: (1) RCT with adult participants, (2) vitamin D administration alone, (3) studies that quantified EF using commonly applied methods including ultrasound, plethysmography, applanation tonometry and laser Doppler.  Results: Sixteen articles reporting data for 1177 participants were included. Study duration ranged from 4 to 52 weeks. The effect of vitamin D on EF was not significant (SMD: 0.08, 95 % CI −0.06, 0.22, p = 0.28). Subgroup analysis showed a significant improvement of EF in diabetic subjects (SMD: 0.31, 95 % CI 0.05, 0.57, p = 0.02). A non-significant trend was found for diastolic blood pressure (β = 0.02; p = 0.07) and BMI (β = 0.05; p = 0.06).  Conclusions: Vitamin D supplementation did not improve EF. The significant effect of vitamin D in diabetics and a tendency for an association with BMI may indicate a role of excess adiposity and insulin resistance in modulating the effects of vitamin D on vascular function. This remains to be tested in future studies

Studies on the regulation of endothelial nitric oxide synthase in endothelial dysfunction

Ischaemic heart disease and cerebrovascular disease are the leading causes of morbidity and mortality in the world. The underlying progression of the disease is linked to a reduction in the bioavailability of nitric oxide. One factor contributing to this is an increase in the production of superoxide radicals. A combination of increased oxidative stress, inappropriate lipid metabolism and cell death sets the stage for what will subsequently develop into atherosclerosis. The process of atherogenesis can slow down if patients at risk are identi ed early, receive the necessary pharmacological treatment and change to a healthier lifestyle. The aim of the following studies was to identify whether the uptake, synthesis and recycling of tetrahydrobiopterin (BH4), the essential co-factor of endothelial nitric oxide synthase (eNOS), could in uence oxidative stress in human vasculature. We also sought to elucidate whether endothelin-1 (ET-1), a potent vasoconstrictor, played an important role in oxidative stress in human vasculature and the potential mechanisms underlying this in uence. In Study I, 49 patients with coronary artery disease took part in a placebo-controlled clinical trial with the aim of determining the mechanisms of exogenous BH4 in relation to vascular function. Oral BH4 treatment signi cantly elevates the levels of BH4 in blood, but this effect is limited by the rapid systemic oxidation of exogenous BH4. The ratio of reduced to oxidised biopterins in blood and vascular tissue is unchanged by exogenous BH4 treatment, resulting in no net effect on vascular superoxide production or endothelial function. In Study II, the aim was to explore the regulation of endogenous BH4 and subsequent effects on endothelial function in patients with coronary artery disease. In three clinical models and one in vitro model, involving 465 subjects, we observed that an inability to increase vascular BH4 synthesis leads to signi cant impairment of endothelial function. In Study III, the aim was to explore the role of ET-1 in endothelial dysfunction, speci cally with regard to superoxide production. ET-1 increases superoxide production in human coronary artery bypass grafts via a receptor-driven mechanism involving, the largest contributor of superoxide in the vascular wall, nicotine amide dinucleotide phosphate (NADPH) oxidase. In Study IV, I applied what I had learned from Study I and Study II and sought to further delineate whether endothelin-1 in uences biopterin homeostasis in both human and animal tissues. ET-1 did not have any effect on BH4 in human coronary artery bypass grafts or resistance arteries, endothelial cells and mice with an over-expression of ET-1 in the endothelium (ET-transgenic mice)

A Decreased Level of Serum Soluble Klotho Is an Independent Biomarker Associated with Arterial Stiffness in Patients with Chronic Kidney Disease

Background: Klotho was originally identified in a mutant mouse strain unable to express the gene that consequently showed shortened life spans. In humans, low serum Klotho levels are related to the prevalence of cardiovascular diseases in community-dwelling adults. However, it is unclear whether the serum Klotho levels are associated with signs of vascular dysfunction such as arterial stiffness, a major determinant of prognosis, in human subjects with chronic kidney disease (CKD). Methods: We determined the levels of serum soluble Klotho in 114 patients with CKD using ELISA and investigated the relationship between the level of Klotho and markers of CKD-mineral and bone disorder (CKD-MBD) and various types of vascular dysfunction, including flow-mediated dilatation, a marker of endothelial dysfunction, ankle-brachial pulse wave velocity (baPWV), a marker of arterial stiffness, intima-media thickness (IMT), a marker of atherosclerosis, and the aortic calcification index (ACI), a marker of vascular calcification. Results: The serum Klotho level significantly correlated with the 1,25-dihydroxyvitamin D level and inversely correlated with the parathyroid hormone level and the fractional excretion of phosphate. There were significant decreases in serum Klotho in patients with arterial stiffness defined as baPWV >= 1400 cm/sec, atherosclerosis defined as maximum IMT >= 1.1 mm and vascular calcification scores of ACI>0%. The serum Klotho level was a significant determinant of arterial stiffness, but not endothelial dysfunction, atherosclerosis or vascular calcification, in the multivariate analysis in either metabolic model, the CKD model or the CKD-MBD model. The adjusted odds ratio of serum Klotho for the baPWV was 0.60 (p = 0.0075). Conclusions: Decreases in the serum soluble Klotho levels are independently associated with signs of vascular dysfunction such as arterial stiffness in patients with CKD. Further research exploring whether therapeutic approaches to maintain or elevate the Klotho level could improve arterial stiffness in CKD patients is warranted

Oxidative stress and epigenetic regulation in ageing and age-related diseases

Recent statistics indicate that the human population is ageing rapidly. Healthy, but also diseased, elderly people are increasing. This trend is particularly evident in Western countries, where healthier living conditions and better cures are available. To understand the process leading to age-associated alterations is, therefore, of the highest relevance for the development of new treatments for age-associated diseases, such as cancer, diabetes, Alzheimer and cardiovascular accidents. Mechanistically, it is well accepted that the accumulation of intracellular damage determined by reactive oxygen species (ROS) might orchestrate the progressive loss of control over biological homeostasis and the functional impairment typical of aged tissues. Here, we review how epigenetics takes part in the control of stress stimuli and the mechanisms of ageing physiology and physiopathology. Alteration of epigenetic enzyme activity, histone modifications and DNA-methylation is, in fact, typically associated with the ageing process. Specifically, ageing presents peculiar epigenetic markers that, taken altogether, form the still ill-defined “ageing epigenome”. The comprehension of mechanisms and pathways leading to epigenetic modifications associated with ageing may help the development of anti-ageing therapies

Diabetic Cardiovascular Disease Induced by Oxidative Stress.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with diabetes mellitus (DM). DM can lead to multiple cardiovascular complications, including coronary artery disease (CAD), cardiac hypertrophy, and heart failure (HF). HF represents one of the most common causes of death in patients with DM and results from DM-induced CAD and diabetic cardiomyopathy. Oxidative stress is closely associated with the pathogenesis of DM and results from overproduction of reactive oxygen species (ROS). ROS overproduction is associated with hyperglycemia and metabolic disorders, such as impaired antioxidant function in conjunction with impaired antioxidant activity. Long-term exposure to oxidative stress in DM induces chronic inflammation and fibrosis in a range of tissues, leading to formation and progression of disease states in these tissues. Indeed, markers for oxidative stress are overexpressed in patients with DM, suggesting that increased ROS may be primarily responsible for the development of diabetic complications. Therefore, an understanding of the pathophysiological mechanisms mediated by oxidative stress is crucial to the prevention and treatment of diabetes-induced CVD. The current review focuses on the relationship between diabetes-induced CVD and oxidative stress, while highlighting the latest insights into this relationship from findings on diabetic heart and vascular disease

The impact of fish oil fatty-acids on post-prandial vascular reactivity.

Progressive loss of vascular reactivity and increased vascular tone with age are being increasingly recognised as significant cardiovascular disease (CVD) risk factors. The vasculature has emerged as a target for dietary strategies to modify these progressions. Our previous data suggest that inclusion of fish oil in a high-fat test meal improves postprandial vascular reactivity in healthy men. The primary aim of this project was to determine the individual effects of the fish oil fatty acids, eicosapentaenoic acid (EPA) versus docosahexaenoic acid (DHA) on post-prandial vascular reactivity and to identify underlying molecular mechanisms of these effects. In this study, the acute effects of a single dose (4.16g) of EPA, DHA and placebo oil on postprandial vascular reactivity were determined in men categorised as being at a 1.5 relative risk of CVD in a double-blind randomised crossover trial. Measures of vascular tone and function, alongside an endothelium dependent measure of vascular reactivity, were taken along with blood samples, at baseline and at 4 hours in order to coincide with the anticipated peak plasma concentration of these fatty acids. These blood samples were utilised for assessment of biomarkers associated with changes in vascular tone and postprandial whole blood culture (WBC). WBC was conducted to investigate the effect of changes in the postprandial lipidome, dependent on EPA and DHA consumption, on cytokine production. Response to intervention according to genotype was also determined retrospectively. We observed that DHA (p=0.04) but not EPA (p=0.06) significantly reduced Augmentation Index (AI) postprandially when compared to control. AI was reduced by 13.3% and 11.3% in response to DHA and EPA respectively. In addition, our data shows for the first time, that levels of the vasoactive n-3 PUFA epoxide and diol metabolites are subject to large changes post consumption of physiological levels of EPA and DHA. Our data also suggests there is wide inter-individual variability in circulating levels of these compounds, which may in part explain inter-individual responsiveness to EPA and DHA. We were not able to observe changes in plasma nitrite or H2S levels postprandially, suggesting that EPA and DHA dependent changes in vascular tone may be mediated in part by their vasoactive epoxide and diol metabolites. However, whole Blood Culture experiments did not show a significant effect on any of the cytokines or growth factors investigated, before or after correction for BMI and AGE. Finally, our investigations of response to treatment by genotype suggested a novel interaction between the PPAR-ƴ rs1801282 polymorphism, DHA consumption and improvements in postprandial triglyceridemia. The findings of this thesis emphasise the differential effects of EPA and DHA in the vasculature and the inter-individual responsiveness to these nutrients

DNA damage: A main determinant of vascular aging

Vascular aging plays a central role in health problems and mortality in older people. Apart from the impact of several classical cardiovascular risk factors on the vasculature, chronological aging remains the single most important determinant of cardiovascular problems. The causative mechanisms by which chronological aging mediates its impact, independently from classical risk factors, remain to be elucidated. In recent years evidence has accumulated that unrepaired DNA damage may play an important role. Observations in animal models and in humans indica

Antioxidant Supplementation in the Treatment of Aging-Associated Diseases

Oxidative stress is generally considered as the consequence of an imbalance between pro- and antioxidants species, which often results into indiscriminate and global damage at the organismal level. Elderly people are more susceptible to oxidative stress and this depends, almost in part, from a decreased performance of their endogenous antioxidant system. As many studies reported an inverse correlation between systemic levels of antioxidants and several diseases, primarily cardiovascular diseases, but also diabetes and neurological disorders, antioxidant supplementation has been foreseen as an effective preventive and therapeutic intervention for aging-associated pathologies. However, the expectations of this therapeutic approach have often been partially disappointed by clinical trials. The interplay of both endogenous and exogenous antioxidants with the systemic redox system is very complex and represents an issue that is still under debate. In this review a selection of recent clinical studies concerning antioxidants supplementation and the evaluation of their influence in aging-related diseases is analyzed. The controversial outcomes of antioxidants supplementation therapies, which might partially depend from an underestimation of the patient specific metabolic demand and genetic background, are presented