Current Vascular Pharmacology - Volume 7, Issue 2, 2009

Four approved plasma preparations are available in most European countries: fresh frozen plasma, lyophilized plasma, solvent/detergent(SD)-treated plasma and methylene blue/light-treated plasma. Evidence of the clinical efficacy of plasma is mainly based on controlled or uncontrolled observational studies, case reports or expert opinion. As definitions of evidence grades used in previous guidelines and recommendations are sophisticated and difficult to apply to clinical routine, we established a simple system involving 2 recommendation strengths (1 and 2) and 3 evidence grades (A, B, C). Plasma is indicated for complex coagulopathy associated with manifest or imminent bleeding, particularly microvascular bleeding, in massive transfusion, disseminated intravascular coagulation and liver disease. With the exception of emergency situations when clotting assay results are not available on time, a clinically relevant coagulopathy must be verified before plasma is administered. The rapid infusion of at least 10 ml of plasma per kg of body weight is required to increase the respective clotting factor or inhibitor levels significantly. Therapeutic plasma exchange with 40 ml of plasma per kg of body weight is the treatment of first choice in acute thrombotic-thrombocytopenic purpura (TTP) or adult hemolytic uremic syndrome (HUS). Rare indications are congenital factor V or FXI deficiency, plasma exchange in neonates with severe hemolysis or hyperbilirubinemia, and filling of the oxygenator in extracorporeal membrane oxygenation in neonates. Prothrombin complex concentrates should be preferred to plasma for the rapid reversal of oral anticoagulation, since plasma is less efficient in this setting. Side effects resulting from the administration of plasma are rare but have to be considered.

Blood pressure (BP) is one of the most important and common vascular risk factors but it is often poorly controlled. Inhibition of the renin-angiotensin-aldosterone system (RAAS) provides beneficial effects in hypertensives. The association of low-dosed diuretics in combination with RAAS blocking agents allows maximum benefit from potassium depletion and control of compensatory increase in renin secretion, so increasing the efficacy and safety of RAAS blockers. Irbesartan is a potent and selective angiotensin II subtype 1 receptor antagonist indicated for use in patients with hypertension, including those with type 2 diabetes mellitus and nephropathy. Once-daily irbesartan administration provides 24h control of BP. In patients with mild-to-moderate hypertension, irbesartan was as effective as enalapril, atenolol and amlodipine, and more effective than losartan and valsartan in terms of absolute reduction in BP and response rate. Irbesartan also induced regression of left ventricular hypertrophy. Moreover, irbesartan 300 mg/day exerts a significant renoprotective effect in hypertensive type 2 diabetic patients. The relative risk of doubling of serum creatinine was significantly lower with irbesartan than amlodipine or placebo. Irbesartan was also effective in non-diabetic nephropatic patients. Moreover, irbesartan has peroxisome proliferator-activated receptor agonistic effects in in vitro studies, and it also demonstrated beneficial effects on inflammatory markers of atherosclerosis and endothelial function. The overall incidence of adverse events is similar to that of placebo. A fixed dose of hydrochlorothiazide (HCTZ) and irbesartan shows additive antihypertensive effect in a dose dependent manner up to HCTZ 25 mg and irbesartan 300 mg with high tolerability in diverse patient groups. Combination effects on end organ protection must be evaluated by broad spectrum studies. Ongoing trials about irbesartan and its combination with diuretics may provide necessary data to interpret the value of this association among others.

Congestive heart failure (CHF) is characterized not only by profound abnormalities in the haemodynamic profile but also by changes in sympathetic cardiovascular function. These neurogenic abnormalities are important features of the disease that can affect the prognosis of CHF and to become a target for therapeutic intervention. This article addresses 4 major issues. It will first examine the evidence that a hyperadrenergic state is a hallmark of CHF, based on data collected via indirect (plasma norepinephrine, power spectral analysis of the heart rate signal) and direct (microneurography, norepinephrine spillover, radioimaging techniques visualizing myocardial neural network) approaches. It will then provide an overview on the central, reflex and metabolic factors potentially responsible for the phenomenon. The review also analyses the clinical consequences of the adrenergic alteration, with particular emphasis on the effects of the sympathetic overdrive on disease progression, arrhythmogenic threshold, adverse clinical outcomes as well as sudden death. The final part of the review will examine the therapeutic implications of the above mentioned findings and discuss the effects of pharmacological and non- pharmacological interventions on the sympathetic abnormalities of the heart failure state.

Stroke is among the most common causes of death and persisting disability and therefore represents a great social and economic burden worldwide. In order to lower this burden it is essential to identify risk factors and respective preventive strategies. Besides the established stroke risk factors (e.g. hypertension, diabetes, hypercholesterolemia, atrial fibrillation) both acute and chronic infectious diseases have emerged as risk factors for stroke. Mainly acute respiratory tract infection but also urinary tract infections independently increase the risk of ischemic stroke. Such additional risk was shown to be highest for infection within 3 days before ischemia and the risk steadily declines with increasing time intervals between infection and stroke. Associations between stroke incidence and mortality and influenza epidemics have been demonstrated. Observational studies showed an inverse association between influenza vaccination and stroke risk; however, interventional studies in this field have not been performed so far. Chronic infections, presently discussed as stroke risk factors mainly include periodontitis and infections with Helicobacter pylori (Hp) and Chlamydia pneumoniae (Cp). Although most respective studies identified these infectious diseases as independent stroke risk factors interventional trials have not been performed so far and causality is not proven, yet. There is preliminary evidence that the number of pathogens to which a subject had been exposed to rather than single pathogens are associated with the risk of stroke or other cardiovascular diseases. Chronic infectious diseases are treatable conditions and their identification as causal contributors to stroke risk could offer new avenues in stroke prevention.

The introduction of ultrasound screening combined with the increasingly elderly population means that the number of small abdominal aortic aneurysms (AAAs) detected is expected to increase over the next decade. At present open or endovascular surgery are the only treatment options for AAA. In this mini-review we discuss the rationale and ongoing attempts to develop non-surgical therapies for AAA.

The use of intravenous (i.v.) antihypertensives in the treatment of cardiovascular-related hypertensive emergencies crosses distinct areas of clinical care and therapeutic applications. From first contact with emergency medical services (EMS) personnel, through the entire course of patient evaluation and care to medication considerations at the time of discharge, the applications for the i.v. antihypertensives are multiple and varied. This article describes the frequently encountered cardiovascular-related conditions found in their respective clinical settings and the utility of various antihypertensive treatment options.

Obesity is a risk factor for complications of atherosclerotic vascular disease such as myocardial infarction and stroke. Recent studies have demonstrated that the vascular risk associated with obesity is correlated particularly with visceral adiposity. These clinical observations indicate that various adipose tissue depots may have differential effects on vascular risk. Cellular constituents of adipose tissue secrete cytokines and chemokines that may affect vascular disease. Visceral fat has been demonstrated to express more inflammatory cytokines than subcutaneous fat in obese states. The adipose tissue secretory profile may reflect the influx of macrophages that has been shown to occur with expansion of fat stores. This macrophage infiltration may lead to a chronic low grade, systemic, inflammatory state. Since circulating markers of inflammation are associated with cardiovascular events, the inflammation triggered by adipose tissue may contribute to increased vascular disease. While the vasculopathic effects of visceral obesity may be best treated by weight loss, long term weight loss is difficult to achieve, even with currently available pharmacotherapies. Therapies that target macrophage accumulation in fat or the adipocyte expression profile may be potentially beneficial in reducing the vascular risk associated with obesity. Further characterization of the factors responsible for promoting atherosclerosis in the setting of visceral obesity may lead to new targets for the prevention of atherosclerosis.

Over the past 20 years, conventional ultrasonography has identified features of the “unstable” carotid plaque. Histological studies have recognized that plaque inflammation and neoangiogenesis play a pivotal role in the developing of the vulnerable plaque. Hence, the growing interest on the biological activities of atherosclerotic lesions leading to cerebrovascular events. The presence of adventitial vasa vasorum and the occurrence of plaque vascularization have been considered as predictors of unstable lesions in cerebrovascular and/or cardiovascular patients. The advent of ultrasound contrast agents has represented a fundamental step in the up-to-date functional evaluation in several fields with minimally invasive procedures. Contrast specific ultrasound modalities are currently used with excellent results in oncology, in cardiology and in vascular diseases. Contrast carotid ultrasound is an emerging imaging technique, able to depict in vivo new functional information on plaque activity and vascularization that may add further new data on the actual condition and future cerebrovascular risk. Further studies will provide a better clarification of the degree of neo-angiogenesis. A future strategy could be represented by the monitoring of plaque neoangiogenesis in order to detect the possible pharmacological effects on plaque remodeling.

The 5-lipoxygenase (5-LO) pathway is responsible for the production of leukotrienes (LTs), inflammatory lipid mediators which play a role in innate immunity. More recently, a pivotal role of LTs in ischemia-reperfusion and shock injury has been suggested. In fact, these pathological conditions are characterized by a severe neutrophil infiltration that gives rise to tissue injury and 5-LO metabolites control neutrophil recruitment in injured tissue by the modulation of adhesion molecule expression. The aim of this review is to analyze the results reported in the literature on the role of 5-LO pathway, with particular regard to LTs, in these pathological conditions. A better understanding of the mechanisms underlying the role of the 5-LO enzyme and/or its metabolites in the regulation of neutrophil trafficking, might open new perspectives in the therapy of organ dysfunction and/or injury associated with shock and ischemia-reperfusion injury.

Cardiovascular diseases are the most common cause of mortality and morbidity accounting for more than 40% of total mortality in Western countries, most of which is due to acute coronary syndromes (ACS), including ST and non- ST elevation myocardial infarction. An optimal pharmacological approach in these patients is of major importance with a particular emphasis on the antiplatelet regimen, which remains the cornerstone of the initial ACS treatment at hospital admission and during percutaneous coronary interventions (PCI). This review briefly discusses the pathogenesis of ACS, and updates the available pharmacological antithrombotic strategies with a particular focus on aspirin and clopidogrel resistance, which has caused major concern, especially in the modern era of interventional cardiology. Persistent platelet reactivity despite aspirin or clopidogrel intake is probably a risk factor for the recurrence of ischemic events. Despite a lack of uniformly accepted definitions of aspirin and clopidogrel resistance, we provide an objective description of what is already proved and what remains to be established. In clopidogrel poor-responders, preliminary data suggest that increasing the loading dose might be beneficial prior to PCI, while trials on the potential benefit of an increased maintenance dose after PCI are ongoing. Overall, data on the mechanisms and the management of platelet hyperactivity or antiplatelet drug biological resistance are still scarce and further studies are needed.

Cardiovascular disease remains the leading cause of death and disability in industrialized nations. The risk of cardiovascular disease is significantly reduced by lifestyle choices that promote cardiovascular health. Epidemiological data demonstrate that poor dietary choices, lack of exercise, smoking, obesity, stress, and pollution all increase cardiovascular risk. Poor habits and choices also have been shown to have adverse effects on vascular endothelial homeostasis leading to the development of endothelial dysfunction. Endothelial dysfunction includes broad regulatory changes leading to the expression of a vasoconstrictive, pro-thrombotic, and pro-inflammatory phenotype of the vascular endothelium. Interest in assessing lifestyle interventions as they relate to endothelial function has been encouraged by data demonstrating that measurements of endothelial function in easily accessible vascular beds such as the brachial artery correlate with risk for future cardiovascular events. Given the logistical difficulties and costs of performing large scale clinical trials assessing the ability of many lifestyle interventions designed to reduce cardiovascular risk, employing measures of endothelial function as a surrogate outcome for cardiovascular risk has allowed researchers to determine the biological plausibility of epidemiological data in this area with smaller studies. Newer study techniques, including genomic methodologies, now allow for better delineation of the mechanisms by which lifestyle choices affect the vascular endothelium and of the role of genetic variation in modifying these effects. This review discusses the effects of lifestyle choices on vascular endothelial function, the role and relevance of using studies that assess endothelial function in assessing cardiovascular risk, and future research directions in this area.

OBJECTIVE: In order to provide an overview of current knowledge, the literature was systematically examined for clinical studies, which evaluate the safety and effectiveness of bosentan in pediatric pulmonary arterial hypertension (PAH). SOURCES: 3 databases (MEDLINE, EMBASE and BIOSIS) were searched for the period January 2000 - October 2007 using the key words “pulmonary arterial hypertension”, “bosentan”, and “pediatric patients/children”. RESULTS: Of 165 identified publications, 21 clinical studies were selected: 1 interventional prospective, 6 observational prospective, 5 observational retrospective, and 9 case reports/case series. In the absence of controlled trials, these 21 studies represent the current evidence on the effectiveness and safety of bosentan in the treatment of pediatric PAH. Bosentan appears to improve long-term functional status and hemodynamics in children with PAH but improvement in exercise capacity is not consistently demonstrated. Promising results are reported for the combination of bosentan with other PAHspecific treatments although guidelines for instituting combination therapy have not been defined. Overall, no safety concern is raised by these studies; adverse events, including liver enzyme elevations, appear to be less frequent than reported in the adult PAH clinical trials. CONCLUSION: Recent experience, although uncontrolled, suggests that bosentan is a well-tolerated and effective therapy for pediatric PAH.

Atherosclerosis is now recognised as a chronic inflammatory disease occurring within the artery wall and ultimately responsible for myocardial infarction, stroke and peripheral vascular disease. A crucial step in atherogenesis is the infiltration of monocytes into the subendothelial space of large arteries where they differentiate into macrophages and become functionally active. Macrophage accumulation within plaques is a hallmark of all stages of atherosclerosis, indeed recent studies have shown their presence has the potential to act as a non-invasive marker of disease activity and plaque stability. Activated macrophages are major players in all stages of lesion development. They not only accumulate lipids but also express effector molecules that are pro-inflammatory, cytotoxic and chemotactic. Furthermore, they secrete enzymes that degrade extracellular matrix leading to plaque destabilisation and increased risk of rupture. However, macrophages are heterogeneous and when appropriately activated they have the potential to drive tissue remodelling and ultimately vascular repair. Pharmacological modulation of macrophage activities therefore represents an important strategy for the prevention and treatment of atherosclerosis and other inflammatory diseases. The aim of this review is to give a brief overview of our current understanding of macrophage activation, distribution and function within inflamed tissue. This will provide the basis for highlighting already available and future methods to exploit specifically activated macrophages as diagnostic and therapeutic targets for atherosclerosis.

Primary aldosteronism is the most common cause of secondary hypertension, accounting for about 10% of all forms of high blood pressure. Life-time pharmacological therapy is the treatment of choice for primary aldosteronism due to idiopathic adrenal hyperplasia (IHA), while adrenalectomy is effective in curing most patients with an aldosterone producing adenoma (APA). Far from being a benign form of hypertension, primary aldosteronism is characterized by the development of cardiovascular renal and metabolic complications, including left ventricular hypertrophy, myocardial infarction, atrial fibrillation and stroke, microalbuminuria, renal cysts as well as metabolic syndrome, glucose impairment and diabetes mellitus. We review recent clinical experience with the above mentioned complications and long-term outcomes of blood pressure normalization and cardiac, renal and gluco-metabolic complications in patients with primary aldosteronism, after medical treatment with mineralocorticoid receptor antagonists and surgical treatment. We conclude that removal of adrenal adenoma results in normalization of the renin-angiotensin-aldosterone system (RAAS) and of kalaemia and improvement of blood pressure levels in all patients. Complete resolution of hypertension is achieved in nearly half of treated patients. Moreover, unilateral adrenalectomy is the best treatment to have the regression of cardiovascular, renal and metabolic complications in patients with APA. On the other hand, targeted medical treatment with aldosterone antagonists improves blood pressure control and appears able to prevent the progression of cardiac and metabolic complications in patients with IHA.

Vascular embolisation agents are particles or fluids that can be released into the bloodstream through a catheter to mechanically and/or biologically occlude the target vessel, either temporarily or permanently. This definition excludes vessel-blocking agents or devices such as balloons and coils, which are positioned at the target site, as opposed to released in the bloodstream. Vascular embolisation agents are available as solids, liquids and suspensions. Careful selection of the agent based on the size and calibre of the target vessel ensures that the occlusion is confined to the desired site. In this review, we discuss the 2 main categories of embolisation agents: particles (either non-spherical or microspherical), which are the most widely used; and liquids (glues, gels, sclerosing agents and viscous emulsions). For each agent, we review the characteristics, mechanisms of action, main indications and modalities of use, advantages and drawbacks. The use of embolisation in clinical practice requires a thorough understanding of the behaviour (rheology and vascular topology) and biocompatibility of each agent. To improve the accuracy of targeting, we need new, more sophisticated, bioactive agents, which are being developed.