Current Vascular Pharmacology - Volume 8, Issue 1, 2010

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As an alternative to the inconvenient and labor intensive traditional anticoagulants, Factor Xa inhibitors may offer new options for the prevention and treatment of acute coronary syndromes (ACS) and venous thromboembolism (VTE). Fondaparinux, an indirect FXa inhibitor, has equivalent efficacy but decreased bleeding risk. It has been recommended by the American College of Cardiology (ACC)/American Heart Association (AHA) as the preferred anticoagulant in ACS patients with higher bleeding risk managed with a noninvasive strategy. Based on the composite results of several clinical trials, fondaparinux is also recommended for VTE prevention in the setting of major orthopedic surgery. Rivaroxaban, a direct FXa inhibitor, appears to have at least equal efficacy and safety to established anticoagulants in the prevention of VTE. With advantages such as oral administration and a wide therapeutic window, it may provide a useful alternative to current anticoagulants. Ongoing studies are exploring its use in treatment of VTE and ACS, as well as prevention of stroke among patients with atrial fibrillation. In this review, we examine the key recent studies on efficacy and safety of FXa inhibitors in ACS and VTE management.

Visfatin is highly expressed in adipose tissue (mainly by the stromal cells), but it is also ubiquitously present in most tissues. Visfatin, which plays a role in nicotinamide adenine dinucleotide (NAD) biosynthesis, has been implicated in inflammatory states. Controversial results exist about the expression, circulating levels and the role of visfatin in atherosclerosis-related diseases. Most studies showed increased levels of visfatin in diabetes mellitus, obesity, hypertension, renal and cardiovascular disease. However, other studies reported lower levels of visfatin in these diseases. The discrepancies in clinical studies may be attributed to the multifactorial regulation of visfatin. There is evidence that visfatin expression and circulating levels are influenced by fat area and distribution, inflammatory state, renal function, iron metabolism, hormones as well as several other factors. Furthermore, discrepancies and lack of correlation between commercially available visfatin assays have been reported. More research is needed to better understand the factors that control its synthesis/release and to evaluate the role of visfatin in atherosclerosis-related disease. Large studies with homogeneous populations will probably be needed to answer these questions. Whether visfatin will eventually become a therapeutic target remains to be established.

Stroke is a significant cause of long-term disability. Currently, once damage from a stroke is established little can be done to recover lost function. Cell transplantation emerged as possible alternative therapy, on the basis of animal studies showing that cells transplanted into the brain not only survive but also lead to functional improvement in different neurodegenerative diseases. Stem cells have been tested in stroke patients as a possible treatment option. While initially stem cells seemed to work by a “cell replacement” mechanism, it is emerging that cell therapy works mostly by providing trophic support to the injured tissue and brain, fostering both neurogenesis and angiogenesis. This review summarizes clinical studies on stem cell transplantation in stroke patients to evaluate the safety, feasibility of administration and tolerability of this experimental treatment. At present there is little evidence to assess the applicability of this treatment in stroke patients and well designed clinical trials are necessary to evaluate safety and toxicity as well as optimal cell type, route and time of delivery.

Cerebrovascular diseases and especially ischemic stroke are a leading cause of death. They occur mostly due to an insufficient oxygen (O2) supply to the central neural tissue as a result of thromboembolic events and/or obstructive vessel disease. The primary damage of the brain tissue cannot be restored. However, adequate therapy could minimize secondary impairment of brain tissue and restore neuronal function in the so-called “penumbra region”. Apart from reopening occluded vessels, additional O2 supply is essential for survival of malfunctioning neural tissue. Breathing of 100% O2 under hyperbaric conditions, hyperbaric oxygenation (HBO), is the only method to increase the O2 concentration in tissue with impaired blood supply. Experimental as well as clinical studies have reported a positive effect of HBO therapy. Survival rate has increased under HBO therapy and neurological outcome has improved. The optimal levels of pressure as well as duration and numbers of HBO sessions need to be specified to avoid undesirable effects. Unfortunately, many questions remain unanswered before routinely recommending HBO as additional therapy in clinical practice. In this review we consider the (patho-)physiological background of HBO-therapy, the latest results of experimental and clinical studies and stress the evidence in patients with cerebrovascular disease.

The incidence of dementia is increasing dramatically with the ageing population. Increasing evidence indicates that vascular disease is associated with cognitive decline and with the most common form of dementia, Alzheimer's disease (AD). Cardiovascular risk factors such as hyperlipidaemia, hypertension and type 2 diabetes have attracted attention as potential targets in the prevention of dementia. The present review aims to provide a concise overview of the recent advances linking vascular disease with dementia (with a particular focus on AD) and to examine the evidence for efficacy, where possible, for utilising vascular pharmacotherapy as a treatment option for dementia.

Monoclonal antibodies have been developed to optimize treatment effects in various malignant and nonmalignant conditions, by selectively targeting key components of the underlying pathophysiologic processes. Rituximab, a chimeric anti-CD20 antibody has revolutionized treatment of malignant lymphomas, extending remission rates, diseasefree survival and overall survival, all achieved with minimal toxicity. Bevacizumab, a humanized monoclonal antiantibody with anti-angiogenetic properties through inhibition of vascular endothelial growth factor, was initially approved for the adjuvant treatment of metastatic colorectal cancer with promising results. Eculizumab, a selective inhibitor of the complement terminal cascade, was the first etiologic treatment of intravascular hemolysis in patients with the rare, acquired paroxysmal nocturnal hemoglobinuria (PNH). Although none of these agents has direct antithrombotic properties, there is increasing evidence of their preemptive and therapeutic use in rare acquired thrombotic disorders, including thrombotic thrombocytopenic purpura (TTP), central retinal vein occlusion (CRVO) and PNH-associated thrombophilia. This brief review aims to discuss hopes and pitfalls of these new approaches in the context of the underlying mechanisms that lead to thrombosis in these disorders.

It is well known that high salt intake induces hypertension and cardiovascular damage, while dietary potassium supplementation counteracts these harmful effects. Actually, the protective effect of potassium is strengthened with excess salt as compared with salt depletion. Although the precise mechanisms have not been fully elucidated, in our previous reports, the antihypertensive effect of dietary potassium was accompanied by sympathetic nerve inhibition in salt-sensitive hypertension. Also, potassium supplement suppressed salt-induced insulin resistance. These effects of dietary potassium can explain its cardio- and vasculo-protective action in addition to the potassium supplementation-induced decrease saltinduced rise of blood pressure. On the other hand, salt-sensitive hypertension is associated with reactive oxygen species (ROS) overproduction. Moreover, sympathoexcitation can be induced by central ROS upregulation and insulin resistance can be caused by ROS excess in the target organs of insulin, such as skeletal muscle. Conversely, the seemingly different actions of potassium can be explained by the antioxidant effect of dietary potassium; in our recent studies, potassium supplementation inhibits salt-induced progress of cardiac diastolic dysfunction and vascular neointima formation by cuff placement around arteries, associated with the inhibition of regional ROS overproduction, in salt-sensitive hypertension. Thus, it is possible that dietary potassium protects against salt-induced cardiovascular damage by the reduction of ROS generation and by central sympatholytic action and amelioration of insulin resistance induced through its antioxidant effect.

Elevated levels of serum homocysteine (Hcy) resulting in hyperhomocysteinemia (HHcy) have been implicated in cardiac pathological conditions including: coronary heart disease (CHD), acute myocardial infarction, arrhythmogenesis and sudden cardiac death (SCD). The mechanisms by which HHcy leads to arrhythmogenesis and SCD are unknown. Novel findings indicate that Hcy is an agonist of the N-methyl-D-aspartate receptor (NMDA-R), known to be present in cardiac tissue, and when activated, increases intracellular calcium leading to increased cell excitability. Also, HHcy induces oxidative stress in cardiac cells and activates matrix metalloproteinases (MMPs) that degrade cell membranes and proteins. Here we review the literature relevant to HHcy-induced oxidative stress leading to cardiac tissue remodelling that may adversely affect cell-to-cell impulse conduction, in particular on the heart's specialized conduction system, and may provide substrate for arrhythmogenesis and SCD. Efficacy of B vitamin supplementation in patient populations with HHcy and CHD is also reviewed.

Introduction: This paper aims to summarize the scientific rationale and future perspectives in the development of effective matrix metalloproteinase (MMP) modulators in the management of patients with arterial and venous disease. Methods: Pubmed, Embase and Cinahl databases were searched using the search terms ‘MMP’, ’matrix metalloproteinase’, ‘arterial disease’, ‘venous disease’, ‘aneurysm’, ‘vascular disease’, ‘atherosclerosis’ and ‘varicose veins’. Articles focussing on aneurysm disease, peripheral arterial disease, carotid stenosis and venous disorders were included. Results: Animal studies assessing MMP expression have demonstrated that MMP-2 and MMP-9 may contribute to arterial aneurysm formation and in atherosclerosis. Human studies and animal models have shown that MMP-3 and MMP-9 may have a protective role against plaque development and destabilization whereas MMP-12 might promote these changes. In venous disease, increased expression of MMP-1, MMP-9 and MMP-13 have been shown in human varicose veins. MMP- 2 and MMP-9 were also shown to be upregulated in experimentally induced venous hypertension and higher concentrations of MMP-2 in wound exudate and biopsies have been shown to correlate with impaired venous ulcer healing. The use of statins has become widespread in patients with arterial disease and MMP inhibition is likely to contribute to the mechanism of action. More selective MMP modulators are currently being developed, although clinical studies are currently lacking. Conclusions: MMPs have been directly implicated in the pathophysiology of many arterial and venous disorders and remain an important potential therapeutic target. Studies are needed to further develop and demonstrate the clinical benefits of MMP modulating agents.

The expression of the Receptor for Advanced Glycation Endproducts (RAGE) is upregulated at sites of vascular inflammation and plays a crucial role in vessel homeostasis. Soluble RAGE (sRAGE), a truncated soluble form of the receptor, acts as a decoy and prevents the inflammatory response mediated by RAGE activation. sRAGE has recently emerged as a biomarker in several RAGE-mediated vascular disorders, including coronary artery disease, hypertension, diabetic vasculopathy and Kawasaki disease. Given the pivotal role played by RAGE and sRAGE in numerous vascular disorders, there is a growing need to understand how drugs can modulate the RAGE axis in different disease conditions. In this regard, there is evidence to suggest that traditional cardiovascular drugs (statins, thiazolidinediones, ACEinhibitors, AT-1 receptor antagonists) as well as nutraceuticals (grape seed proanthocyanidin extract) could modulate RAGE expression and circulating sRAGE levels in cardiovascular disease states characterized by enhanced RAGE activation. Additionally, the production of genetically engineered sRAGE may hold promise for targeting the activation of RAGE by proinflammatory ligands in the setting of vascular inflammation. The present review considers current vascular drugs as modulators of the RAGE axis, and highlights future directions in the context of RAGE-directed therapy in cardiovascular disease.

The use of oral antiplatelet therapy in reducing vascular events has been extensively studied. Currently available oral antiplatelet agents include aspirin and the thienopyridine P2Y12 receptor antagonists. These classes are combined frequently in the setting of acute coronary syndrome and percutaneous coronary intervention (PCI). Resistance to either or both of these agents is a major concern, as antiplatelet resistance has been linked to an increase in thrombotic events and worse clinical outcomes. As a result, there is a need for newer, more effective antiplatelet agents to address the limitations of currently available therapy. Prasugrel, a third generation thienopyridine, has been approved by both the FDA and European Commission. Two additional P2Y12 agents, ticagrelor and cangrelor are in advanced stages of development. The possible advantages of prasugrel over clopidogrel include a faster onset of action, reduced inter-patient variability and more potent platelet inhibition. Ticagrelor is an oral reversible P2Y12 antagonist with greater platelet inhibition compared with clopidogrel. Cangrelor is being developed as an intravenous P2Y12 antagonist with a very fast onset and offset, which may offer advantages particularly in the setting of coronary intervention. These emerging antiplatelet agents may offer advantages such as faster onset of action, greater potency and reversibility of platelet inhibition. This article summarizes the available clinical data on the upcoming P2Y12 antiplatelet agents in the treatment of coronary artery disease.

Induction of neo-angiogenesis is a fundamental step in many pathological conditions. The therapeutic value of inhibiting angiogenesis is an interesting area of research in oncology, with vascular endothelial growth factor (VEGF) being the most suitable anti-angiogenic target. In the last decade a number of anti-VEGF drugs have demonstrated, especially in combination with standard chemotherapy, clinical efficacy in the treatment of different solid tumor types. As data from clinical trials on anti-VEGF drugs are becoming available, it is increasingly recognized that VEGF, in addition to being a permeability, proliferation, and migration factor, is also a maintenance and protection factor for endothelial cells, being capable of regulating multiple biological functions, i.e. the production of vasoactive mediators and the expression of components of the thrombolytic and coagulation pathways. Consequently, the disturbance of vascular homeostasis by blocking VEGF may lead to endothelial dysfunction and adverse vascular effects, such as venous and arterial thromboembolic events. In preclinical models angiogenesis and the increased expression of VEGF has been associated to altered expression of proinflammatory genes. These genes may be regulated in a biphasic manner, and it is possible that anti-VEGF therapy may disrupt a negative feedback loop that leads to potential in situ thrombus formation. Accordingly, combination treatment with bevacizumab and chemotherapy, compared with chemotherapy alone, was recently associated with an increased risk of thromboembolism. The present review considers the biological mechanisms and clinical impact of thromboembolic complications during anti-angiogenic treatments in cancer patients.

Inflammation is an important process and an underlying mechanism involved in atherogenesis as well as the clinical manifestations following coronary artery disease (CAD). Evidence suggests that chronic heart failure (CHF) is associated with an increased inflammatory process. Pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFa), interleukin-6 (IL-6), interleukin-1 (IL-1) and adhesion molecules are elevated in states of CHF and are related to long term prognosis. Statins are among the most effective compounds reducing morbidity and mortality in patients with, or at increased risk of, CAD. Efficacy and safety of statin treatment has not been validated in patients with CHF. Several studies have reported that statins could be beneficial in patients with CHF. In addition, the beneficial effects of statins have been largely attributed to their anti-inflammatory properties. However, recent randomized, double-blind, placebo-controlled trials reported that statins did not affect clinical outcomes in patients with CHF of any cause. These data support the notion that current immunomodulation approaches in heart failure are not successful. Thus, more large scale clinical trials are required to evaluate the impact of statins on immune imbalance and its restoration in patients with CHF.

Vascular endothelial growth factor (VEGF) is a main regulator of blood vessel growth and plays an important role in promoting endothelial survival and maintaining the microvasculature. The kidney is a highly vascularized organ and has two important microvasculatures; glomerular and peritubular capillaries. Loss of these capillaries is strongly associated with the progression of chronic kidney disease (CKD) to end-stage renal disease. In several kidney disease animal models, VEGF expression in the kidney is decreased and administration of VEGF is protective. Recent clinical observations revealed that blocking VEGF by endogenous inhibitor (soluble Flt-1) in preeclampsia and monoclonal antibody against VEGF in cancer patients cause proteinuria and renal dysfunction. However, plasma VEGF levels in diabetic nephropathy patients are increased and blocking VEGF improved diabetic nephropathy in animal models. Increased plasma VEGF levels have been reported in CKD patients. Deleterious effects of VEGF have been demonstrated in atherosclerosis and sepsis, which are frequent complications in CKD patients. Although administrating VEGF or novel drugs that activate VEGF pathway may improve the progression of CKD, careful monitoring will be required when CKD patients have complications of diabetes, atherosclerosis or sepsis.

This review addresses 2 fields: secondary prevention after cerebral ischaemia of cardiac origin (CICO) and that after cerebral ischaemia of arterial origin (CIAO). The major trial after CICO is the EAFT that showed the superiority of mild oral anticoagulation (INR 2-3) over aspirin and placebo. Despite several more recent trials with ximelagatran (e.g. SPORTIF and ACTIVE-W) the current standard remains mild oral anticoagulation. After CIAO several trials tried to improve the 13% relative risk reduction achieved with aspirin. Attempts with oral anticoagulation were disappointing: high INRs were not safe (SPIRIT), low INRs not effective (WARSS) and with a mild regimen (INR 2-3) the benefits for ischaemic events were cancelled by more major bleeding. Clopidogrel tended to be modestly more effective than aspirin after stroke (CAPRIE), but its combination with aspirin appeared not to be safe (MATCH, CHARISMA). Combination of aspirin with dipyridamole, however, was safe and more effective than aspirin alone (ESPS-2, ESPRIT). Recent American and European guidelines mention both the combination of aspirin and dipyridamole and clopidogrel monotherapy for secondary prevention after cerebral ischaemia of arterial origin. The recent PRo- FESS trial found no differences in the efficacy of aspirin plus dipyridamole and clopidogrel, hence there is no need for major adaptation of the guidelines.

In order to prioritize limited health resources in a time of increasing demands optimal cardiovascular risk stratification is essential. We tested the additive prognostic value of 3 relatively new, but established cardiovascular risk markers: N-terminal pro brain natriuretic peptide (Nt-proBNP), related to hemodynamic cardiovascular risk factors, high sensitivity C-reactive protein (hsCRP), related to metabolic cardiovascular risk factors and urine albumin/creatinine ratio (UACR), related to hemodynamic as well as metabolic risk factors. In healthy subjects with a 10-year risk of cardiovascular death lower than 5% based on HeartScore and therefore not eligible for primary prevention, the actual 10-year risk of cardiovascular death exceeded 5% in a small subgroup of subjects with UACR higher than the 95-percentile of approximately 1.6 mg/mmol. Combined use of high UACR or high hsCRP identified a larger subgroup of 16% with high cardiovascular risk in which primary prevention may be advised despite low-moderate cardiovascular risk based on HeartScore. Furthermore, combined use of high UACR or high Nt-proBNP in subjects with known cardiovascular disease or diabetes identified a large subgroup of 48% with extremely high cardiovascular risk who should be referred for specialist care to optimize treatment.