Current Vascular Pharmacology - Volume 15, Issue 5, 2017

Background: Pharmacotherapy is of increasing interest in peripheral arterial disease (PAD), with novel therapies aiming at different factors contributing to the disease. For antiplatelet therapy, there is no unanimous agreement regarding the nature or duration of optimal antiplatelet therapy so as to reduce major adverse cardiovascular and limb-related events (e.g. repeat interventions and amputations). However, evidence on novel more potent antithrombotic agents, drug combinations and personalized antiplatelet therapy for PAD patients is accumulating. Similarly, statins are now considered as a standard of care in PAD patients, due to their multiple actions which include plaque stabilization, antiinflammatory properties and regression of atheroma. Conclusion: In this article we summarise the evidence on this nephro-endocrine disorder in humans and focus on diagnostic and therapeutic strategies.

Background:Despite recent advances, there is still an unmet need in antithrombotic therapy. New drugs have to overcome old targets, looking for new complementary strategies to counteract thrombus formation and propagation. Since its initial recognition in the 50128;™s, von Willebrand Factor (VWF) has proved to be a contributor in clot formation. The contribution of VWF to platelet adhesion and aggregation is pivotal at high shear rates (i.e. microcirculation and critical artery stenosis), where globular-inactive-VWF elongates in a long chain-active conformation. Particularly, at sites of plaque erosion/disruption the activation of VWF may contribute critically to post-stenotic thrombus formation. In this context, VWF is a potential target of antithrombotic therapies. The plasma concentration of VWF increases in high risk population and predicts cardiovascular (CV) outcome. VWF demonstrates an emerging role in different clinical settings; for example, in valvular heart disease where it has been recently proposed as a new fluido-dynamic marker of disease severity and a predictor of successful correction. Drugs used in daily clinical practice (LMWHs, statins, N-acetylcysteine, glycoprotein IIb/IIIa inhibitors) may have an unselective antagonism on the VWF-pathway. Recently, several 128;œtailor-made128; inhibitors of VWF have been investigated. In animal models and clinical studies monoclonal antibodies, aptamers and nanobodies have been demonstrated to directly interfere with the VWF pathway. These studies proved the powerful antithrombotic property and the acceptable level of safety of this strategy. Conclusion: We provide an overview of the drugs that a have a role in VWF-antagonism, illustrating how they might become a potential option to overcome current limitations of antithrombotic therapy.

Background: Ischaemic stroke in young adults encompasses approximately 5 - 15% of all ischaemic strokes, depending on the selected upper age limit. The key features of the disease, including incidence, risk factors, underlying causes, mortality, outcomes, as well as long-term risks of recurrent events are different from those for elderly patients. There is also evidence indicating that these characteristics may differ ethnically and geographically. It is clinically important to recognize such differences not only for correct diagnosis and treatment, but also for introducing accurate preventive measures. Ethnic differences may stem from several factors, including genetic influence, and necessitate different approaches, such as personalized diagnostic work-up based on patient characteristics. Conclusion: In this review, we summarize and discuss the existing data on the geographic and ethnic differential characteristics of young adult ischaemic stroke.

Background: Pharmacotherapy is of increasing interest in peripheral arterial disease (PAD), with novel therapies aiming at different factors contributing to the disease. For antiplatelet therapy, there is no unanimous agreement regarding the nature or duration of optimal antiplatelet therapy so as to reduce major adverse cardiovascular and limb-related events (e.g. repeat interventions and amputations). However, evidence on novel more potent antithrombotic agents, drug combinations and personalized antiplatelet therapy for PAD patients is accumulating. Similarly, statins are now considered as a standard of care in PAD patients, due to their multiple actions which include plaque stabilization, antiinflammatory properties and regression of atheroma. Conclusion: This review focuses on current evidence available for various antiplatelet regimens and statin therapy for PAD and discusses future perspectives. We consider randomized controlled trials, together with the most important reviews and meta-analyses. Treatment algorithms based on currently available data.

Background: Arterial stiffness, the expression of reduced arterial elasticity, is an effective predictor of cardiovascular disorders. Oxidative stress is an imbalance between exposure to toxic reactive oxygen species (ROS) and antioxidant systems. The increase in reactive nitrogen species (RNS) is termed nitrosative stress. Methodology: We review the main mechanisms and products linking arterial stiffness with oxidative and nitrosative stress in several disorders, focusing on recent experimental and clinical data, and the mechanisms explaining benefits of antioxidant therapy. Oxidative and nitrosative stress play important roles in arterial stiffness elevation in several disorders, including diabetes mellitus, hypertension, metabolic syndrome, obesity, peripheral arterial disease, chronic obstructive pulmonary disease, systemic lupus erythematosus, thalassemia, Kawasaki disease and malignant disorders. Oxidative and nitrosative stress are responsible for endothelial dysfunction due to uncoupling of the nitric oxide synthase, oxidative damage to lipids, proteins and DNA in vascular endothelial cells, associated with inflammation, arteriosclerosis and atherosclerosis. Conclusion: Regular physical exercise, caloric restriction, red wine, statins, sartans, metformin, oestradiol, curcumin and combinations of antioxidant vitamins are therapeutic strategies that may decrease arterial stiffness and oxidative stress thus reducing the risk of cardiovascular events. ROS and RNS represent potential therapeutic targets for preventing progression of arterial stiffness.

Background: Cardiovascular (CV) morbidity and mortality are higher among patients with diabetes mellitus type 2 (T2DM), particularly those with concomitant CV diseases, compared with other populations. In patients with T2DM, intensive glucose lowering reduces microvascular disease, but has a smaller and debated effect on CV events or mortality. In this setting, the US Food and Drug Administration (FDA) required in 2008 that all new agents for the treatment of T2DM should be evaluated in terms of CV safety. Metformin has long been established as first-line pharmacological therapy in patients with T2DM, due to its proven beneficial CV effects. Despite the controversies about the issue of the CV safety of other oral antidiabetic agents such as sulfonylureas (SUs) and thiazolidinediones (TZDs), long-term randomized trials suggested neutral effects of these agents on macrovascular disease. Moreover, there are a number of CV outcome trials designed to determine the long-term CV safety of new glucose-lowering agents, like dipeptidyl peptidase 4 (DPP-4) inhibitors, and sodium glucose cotransporter 2 (SGLT2) inhibitors. Although the results of these trials indicate the CV safety of oral new antidiabetic agents, only one of them (with empagliflozin) has so far reported reduction of CV events. Recently, LEADER (Liraglutide Effect And Action in Diabetes: Evaluation of Cardiovascular Outcome Results - A Long-term Evaluation), a CV outcome trial in diabetic patients by using an injectable glucose-lowering agent (liraglutide) has also reported a reduction in CV outcomes. Conclusion: The present review considers the long-term CV effects of anti-diabetic drugs and updates the relevant randomized CV outcome studies of oral glucose-lowering agents.

Background: Pulmonary hypertension (PH) is a severe disease characterized by a progressive increase in pulmonary vascular resistance, initially due to abnormal pulmonary vasoconstriction in response to endothelial and smooth muscle cells injury. The discovery of new chemical entities having a protective effect on pulmonary artery cells could be meaningful for the treatment of PH. Methods: We evaluated the protective effect of DL0805 derivatives (DL0805-1 and DL0805-2) on pulmonary artery vascular cells, including human pulmonary artery endothelial cells (HPAECs) and human pulmonary artery smooth muscle cells (HPASMCs). DL0805 derivatives are novel ROCKs (Rho-associated coiled-coil forming protein serine/threonine kinases) inhibitors. Treatment of HPAECs with DL0805-2 (10 μM) cultured under a hypoxic environment could significantly reduce the proliferation of cells. Meanwhile, the compounds inhibited the production of reactive oxygen species (ROS) in HPAECs at every dose tested. Results: A Western Blot experiment showed that the protective effect of DL0805 derivatives might result from the down-regulation of RhoA (Ras homolog gene family, member A) expression and the inhibition of ROCKs activity. In addition, the compounds inhibited the proliferation of HPASMCs induced by fetal bovine serum (FBS) or platelet derived growth factor BB (PDGF-BB), and suppressed the F-actin remodeling induced by endothelin. Conclusion: The preliminary results from an immunofluorescence assay showed that DL0805 derivatives inhibited the activity of ROCKs in HPASMCs. The above mentioned results indicated that DL0805 derivatives have a protective effect on pulmonary artery cells, and the underlying mechanisms might be the result of inhibition of RhoA/ROCK signaling pathway.

Background: The clinical manifestations of acute heart failure (AHF) and respiratory infection (RI) frequently overlap in patients presenting with dyspnoea at the emergency department (ED). The neutrophil to lymphocyte (N/L) and platelet to lymphocyte (P/L) ratios have been proposed as diagnostic and prognostic indices in this setting. Objective: To evaluate the ability of N/L and P/L ratios to discriminate the cause of dyspnoea in patients admitted with an initial diagnosis of AHF-RI. Methods: 100 consecutive dyspnoeic chronic heart failure (CHF) patients diagnosed as AHF-RI in the ED of Sotiria Chest Diseases General Hospital were monitored for a series of parameters. The diagnostic efficacy of the registered parameters in discriminating the AHF from RI patients was evaluated. Results: The N/L and P/L ratios did not differ statistically depending on the pharmaceutical therapy applied in the study population, with the exception of furosemide and spironolactone-treated patients, who both had higher ratio values. In the AHF patients, only N/L was influenced by the pharmaceutical treatment administered. Patients with higher N/L ratio values were more likely to have RI-triggereddyspnoea (odds ratio, OR=1.35, 95% confidence interval-CI: 0.99-1.42, p=0.047). ROC curve (receiver operating characteristic curve) analysis revealed a significant ability of the N/L ratio to differentiate pure AHF from RI (area under the curve AUC=0.773, p<00.001, cut-off value N/L= 3.15). Conclusion: The N/L ratio, a cheap and easily assessed biomarker, warrants further investigation as a potential diagnostic tool for the ED physician facing dyspnoeic CHF patients.

Background: The literature shows that a healthy diet, rich in fruits and vegetables, has positive effects on overall cardiovascular risk, protecting against atherosclerosis. Design: A cross sectional study in a population of apparently healthy young-adult men with the aim of investigating dietary determinants of early atherosclerosis, assessed by measuring carotid intima-media thickness (cIMT) and flow-mediated dilation (FMD) of the brachial artery. Methods: 615 males (mean age ± SD: 40.8±9.8 years) without overt atherosclerosis were evaluated. Dietary intake was quantified by the European Prospective Investigation into Cancer and Nutrition (EPIC) questionnaire. Intake of antioxidants was expressed in relation to total caloric intake. Results: Neither absolute, recommended daily allowance or weight-related values of nutritional intake variables were associated with cIMT. Vitamin E to total calories intake (odds ratio, OR=0.08, 95%CI=0.03-0.89) was inversely associated with impaired FMD. Non-nutritional correlates of FMD <10% were: age (OR=1.02, 95%CI=1.0-1.05) and waist circumference (OR=1.03, 95%CI=1.0-1.06), and those of cIMT >00.8 mm were age (OR=1.10, 95%CI=1.05-1.15), pack-years (OR=1.02, 95%CI=1.0-1.04), C-reactive protein (OR=1.17, 95%CI=1.04-1.33) and total cholesterol (OR=1.01, 95%CI=1.0-1.02). Conclusion: Differences in the factors correlating with cIMT >0.8 mm and FMD <10% might have implications for cardiovascular risk reduction. A lower antioxidant to caloric intake ratio might be a risk factor for impaired FMD.

Background: Overexpression of inducible nitric oxide synthase (iNOS) is a key link between high-fat (HF) diet induced obesity and cardiovascular disease. Oestradiol has cardioprotective effects that may be mediated through reduction of iNOS activity/expression. Methods: In the present study, female Wistar rats were fed a standard diet or a HF diet (42% fat) for 10 weeks. iNOS gene and protein expressions were measured in heart tissue. HF-fed rats exhibited a significant increase in cardiac iNOS mRNA by 695% (p<0.05), iNOS protein level by 248% (p<0.01), without changes in nitrate/nitrite levels. Expression of CD36 protein in plasma membranes was increased by 37% (p<0.05), while the concentration of free fatty acids (FFA) was reduced by 25% (p<0.01) in HF-fed rats. Expression of the p50 subunit of nuclear factor-28;‘B (NF28;‘B-p50) in heart was increased by 77% (p<0.01) in HF-fed rats. Expression of protein kinase B (Akt) and extracellular signalregulated kinases 1/2 (ERK1/2) were unchanged between the groups. There was a significant increase in the ratio of phospho-Akt/total Akt but not for phospho-ERK1/2/total ERK1/2 in HF-fed rats. Estrogen receptor-28; levels (by 50%; p<0.05) and serum oestradiol concentrations (by 35%; p<0.05) were shown to be significantly reduced in HF-fed rats. Our results revealed that a HF diet led to increased iNOS expression, most likely via a mechanism involving Akt and NFΚB-p50 proteins. Decreased levels of oestradiol and ERα protein in the HF-fed group, in combination with increased iNOS levels are consistent with the hypothesis that oestradiol has a cardioprotective effect through its ability to regulate iNOS expression.