Current Vascular Pharmacology - Volume 12, Issue 3, 2014

Antithrombotic medication is a cornerstone of acute ischemic stroke treatment and secondary prevention. The efficacy of thrombolysis with alteplase in acute stroke has been demonstrated in several clinical trials. This safe and costeffective therapy has transformed the practice of stroke care and has led to subsequent trials of other antithrombotic medications for treatment of ischemic stroke in the acute phase. These antithrombotics include thrombolytic, antiplatelet and anticoagulant agents. While, no other medication has yet demonstrated adequate efficacy, our current and evolving understanding of infarct expansion, ischemic penumbra, collateral circulation and the blood brain barrier is allowing testing of antithrombotic medications tailored to individual patient pathophysiology in clinical trials. This understanding accompanies developments in neuroimaging and organization of stroke care that allow for wide-spread recruitment in these trials. Alteplase remains the mainstay treatment of arterial acute ischemic stroke; however, anticoagulation is the standard therapy for cerebral venous sinus thrombosis. Antithrombotic use in acute stroke, arterial and venous, has demonstrated efficacy but leaves many questions unanswered. This patient population is a fertile ground for novel research, especially as it relates to; combination antithrombotic therapy, combination of pharmacological and mechanical thrombolysis, and the transition to secondary prevention. Here we review the current antithrombotics in the acute phase of ischemic stroke highlighting the evidence-base and areas of uncertainty.

Secondary prevention of atherosclerotic stroke and transient ischemic attack includes both conventional approaches to vascular risk factor management (blood pressure lowering, cholesterol reduction with statins and smoking cessation), antiplatelet therapy and more specific interventions, such as carotid revascularization. The objective of this review is to discuss effective interventions for optimal secondary prevention of atherosclerotic stroke.

Atrial fibrillation (AF) confers a 4.5% risk of stroke per year. The risk of stroke increases with various risk factors and until recently, warfarin has been the gold standard of thromboembolism prophylaxis in AF for many years. The dosage of warfarin requires regular adjustment dependent on the INR, to keep within a narrow therapeutic range of 2.0- 3.0. The INR can be altered by concomitant drugs, foods and alcohol and requires inconvenient blood monitoring. Underanticoagulation places patients at risk of stroke, whilst over-anticoagulation confers significant bleeding risk. Consequently approximately half who would benefit from oral anticoagulation do not have it prescribed. Novel oral anticoagulants with predictable pharmacokinetics and improved efficacy and safety profiles are currently being developed for stroke prevention in AF. Three novel oral anticoagulants have just completed Phase III trials for stroke prevention, all with impressive results; the direct thrombin inhibitor, dabigatran and the oral factor Xa inhibitors, rivaroxaban and apixaban.

Long term treatment of venous thromboembolism is essential to complete therapy of the index episode and to reduce recurrences. Vitamin K antagonists are the mainstay for the long term treatment of venous thromboembolism for the majority of the patients as they allow oral administration. Low-molecular weight heparins are recommended for the long term treatment of cancer patients. The duration of long term anticoagulation depends on the features of the index venous thromboembolism and on the presence of associated risk factors. Patients at high risk for recurrence – mainly those who suffered unprovoked venous thromboembolism and those with cancer – should be evaluated for extended anticoagulation. The risk for major bleeding complications and the inconvenience for monitoring, dose adjustment and drug-food interactions are the main constraints for indefinite anticoagulant treatment. New anticoagulants with more favourable efficacy- safety profile and reduced need for monitoring could improve the feasibility of extended anticoagulation.

Pulmonary embolism (PE) is a common and potentially life threatening disease if left untreated. This is due to a natural tendency towards early recurrence of pulmonary emboli which may lead to right ventricular failure. Thus, anticoagulant treatment should be administered to all patients upon high or intermediate clinical probability of acute PE, while awaiting definitive confirmation by imaging procedures. With the exception of severe renal impairment, high bleeding risk, arterial hypotension, and extremes of body weight and age, unfractionated heparin has been replaced by low molecular-weight heparin or fondaparinux given subcutaneously at weight-adjusted doses. In hemodynamically unstable patients with confirmed (high-risk) PE, thrombolysis should be administered without delay; if thrombolysis is absolutely contraindicated or has failed, surgical embolectomy or catheter-based thrombus removal is a valuable alternative. In normotensive (non-high-risk) patients, low-molecular-weight heparin or fondaparinux is adequate treatment in most cases, and thrombolysis is generally not recommended as a first-line therapeutic option. An ongoing randomized trial will determine whether normotensive patients with evidence of right ventricular dysfunction plus myocardial injury may benefit from early thrombolysis. Finally, selected normotensive patients without serious comorbidity or signs of heart failure (low-risk PE) may be candidates for out-of-hospital treatment. This strategy may be facilitated by the use of new oral anticoagulants in the future.

Adipocytes are no longer considered just as cells related to storage of energy and thermoregulation. Now we know that they release a huge number of paracrine and endocrine biologically active molecules. This is also the case for perivascular adipose tissue (PVAT) that surrounds almost all blood vessels in the organism. PVAT secretes the so-called adipo(cyto)kines that, because of its proximity, can easily influence vascular smooth muscle cells. The role of PVAT on vascular function can be both protective and deleterious. Normal healthy PVAT, as present in lean subjects, helps to keep the blood vessels dilated as its presence diminishes the effect of vasocontractile agents. Obesity is associated with an increased mass in PVAT. Excessive adipocyte hypertrophy may result in “adiposopathy” in which PVAT attracts macrophages and becomes a more inflammatory phenotype. This leads to a change in profile of the released adipo(cyto)kines, resulting in a decreased vasorelaxing effect of PVAT, which may be linked to obesity-induced hypertension. It also results in smooth muscle cell migration and proliferation and the development of atherosclerotic lesions. The increased knowledge of PVAT function brings up new targets that can be useful to develop novel therapeutic and preventive strategies for obesity-related cardiovascular diseases. This mini-review presents a general overview of the actual knowledge on the role of PVAT on vascular function and dysfunction in obesity.

Obesity is a metabolic disorder of increasing prevalence worldwide and a risk factor for the development of insulin resistance (IR), metabolic syndrome and type 2 diabetes. Obesity is related to endothelial dysfunction through indirect mechanisms such as IR and the associated risk factors, and through direct mechanisms including the production of proinflammatory adipokines and elevated levels of free fatty acids (FFAs) by adipose tissue. Both clinical and experimental studies using genetic and diet-induced animal models of obesity have consistently shown impaired metabolic, agonistor flow-induced vasodilatations correlated with the amount of visceral adipose tissue and improved by dietary interventions and exercise. Compromised bioavailability of NO due to oxidative stress emerges as a main cause of endothelial dysfunction in obesity. Inflamed adipose tissue due to hypoxia, and in particular perivascular adipose tissue (PVAT), secrete larger amounts of reactive oxygen species (ROS) and adipokines that deteriorate NO signaling pathways. Abnormal production and activity of the vasoconstrictor/proatherogenic peptide endothelin-1 (ET-1) is also a hallmark of the obesity- associated endothelial dysfunction. Obesity, and in particular visceral obesity, is one of the main causes of IR, and the pathogenic factors that induce endothelial dysfunction in the earlier stages of obesity will further deteriorate the insulin signaling pathways in endothelial cells thus leading to blunted vasodilatation and abnormal capillary recruitment and substrate delivery by insulin to the target tissues. The present review is an attempt to summarize the current knowledge and the latest novel findings on the pathogenic mechanisms underlying endothelial dysfunction in obesity, in particular the local contribution of oxidative stress and inflammatory response from PVAT, and its role in the obesity-associated cardiovascular and metabolic complications.

Microvascular abnormalities, both in function and structure, lead to impaired tissue perfusion that may affect multiple tissues and organs and seem to be involved in target-organ damage and complications observed in obesity and insulin resistance. In general, vascular remodeling of small arteries associated to cardiometabolic diseases seems to be hypertrophic and it is associated to increased extracellular matrix deposition, although specific vascular beds might show different structural patterns. The mechanisms by which obesity, insulin resistance and/or hyperinsulimemia determine vascular disease are not clear yet but might include hemodynamic factors such as hypertension, activation of the sympathetic nervous and the renin-angiotensin-aldosterone systems, metabolic factors such as insulin and advanced glycation end products and other factors such as adipokines, inflammation or oxidative stress. Exercise and weight loss as well as blockade of the renin-angiotensin system seem to be efficient actions to correct vascular alterations in patients. This review aims to examine the existing literature on structural alterations in small vessels associated to insulin resistance and obesity. A description about the underlying mechanisms possibly responsible of the vascular alterations is also provided. Moreover, effects of pharmacological and non pharmacological strategies that could modify these vascular alterations are summarized.

This review is focused on the effects of obesity on function and expression of potassium (K) channels in the vasculature. Five families of K channels have been identified in the vascular wall, calcium-activated K (KCa) channels, inward-rectifier K (KIR) channels, ATP-sensitive K (KATP) channels, voltage-gated K (KV) channels and two-pore domain K (K2P) channels. In endothelial cells (EC) and vascular smooth muscle cells (VSMC) opening of K channels leads to hyperpolarisation followed by vasodilatation. In some vascular beds of animal models of obesity, vasodilatation mediated by KCa3.1 and KCa2.3 channels has been reported to remain unaltered or even increased, whereas vasodilatation involving KCa1.1 channel has consistently been reported to be impaired. Changes in expression and function of KIR and KATP channels have also been associated with impaired vasodilatation in animal models of obesity, and therefore activation of these channels may improve endothelial function and reduce the risk of major cardiovascular events. Expression of KV7.x channels is downregulated in small arteries from hypertensive animals and it would be interesting to assess whether these channels contribute to development of hypertension in obese patients. However, the role of KV7.x and K2P channels in regulation of blood pressure remains unexplored compared to other K channels. In conclusion, obesity and metabolic syndrome alter expression, function and sensitivity of vascular K channel subtypes causing smooth muscle dysfunction and probably endothelial dysfunction which makes these patients particularly prone to premature cardiovascular disease. Modulation of K channel activity by use of openers of e.g. KCa and KATP channels may also be attractive to counteract vascular dysfunction observed in obesity.

It is believed that obesity has detrimental effects on the coronary circulation. These include immediate changes in coronary arterial vasomotor responsiveness and the development of occlusive large coronary artery disease. Despite its critical role in regulating myocardial perfusion, the altered behavior of coronary resistance arteries, which gives rise to coronary microvascular disease (CMD) is poorly understood in obesity. A chronic, low-grade vascular inflammation has been long considered as one of the main underlying pathology behind CMD. The expanded adipose tissue and the infiltrating macrophages are the major sources of pro-inflammatory mediators that have been implicated in causing inadequate myocardial perfusion and, in a long term, development of heart failure in obese patients. Much less is known the mechanisms regulating the release of these cytokines into the circulation that enable them to exert their remote effects in the coronary microcirculation. This mini review aims to examine recent studies describing alterations in the vasomotor function of coronary resistance arteries and the role of adipose tissue-derived pro-inflammatory cytokines and adipokines in contributing to CMD in obesity. We provide examples of regulatory mechanisms by which adipokines are released from adipose tissue to exert their remote inflammatory effects on coronary microvessels. We identify some of the important challenges and opportunities going forward.

The incidence of obesity in the population is increasing at an alarming rate, with this comes an increased risk of insulin resistance (IR). Obesity and IR increase an individual’s risk of having a stroke and they have been linked to several forms of dementia. Stroke and dementia are associated with, or exacerbated by, reduced cerebral blood flow, which has recently been described in obese patients. In this review we will discuss the effects of obesity on cerebral artery function and structure. Regarding their function, we will focus on the endothelium and nitric oxide (NO) dependent dilation. NO dependent dilation is impaired in cerebral arteries from obese rats, and the majority of evidence suggests this is a result of increased oxidative stress. We will also describe the limited studies showing that inward cerebral artery remodeling occurs in models of obesity, and that the remodeling is associated with an increase in the damage caused by cerebral ischemia. We will also discuss some of the more paradoxical findings associated with stroke and obesity, including the evidence that obesity is a positive factor for stroke survival. Finally we will discuss the evidence that links these changes in vascular structure and function to cognitive decline and dementia.

Insulin resistance and diabetes are current clinical concerns due to their increasing prevalence in western societies and in developing countries. Cardiovascular alterations, affecting both macro- and microcirculation, are among the major causes of illness and premature death within patients with insulin resistance or diabetes. However, the detrimental effects of insulin resistance and diabetes in the lungs are less clinically apparent, or at least masked by the progression of these metabolic diseases on other target organs. Epidemiological and experimental data suggest a link between pulmonary arterial hypertension and diabetes. Thereby, hemodynamic derangements in uncontrolled diabetes or insulin resistance are predisposing factors leading to early pulmonary alterations that in association with a second hit might accelerate the onset of pulmonary vascular disease and pulmonary hypertension. The present article reviewed the current knowledge about the effects of insulin resistance and diabetes in a territory which has received little attention until recently: the pulmonary circulation.

Heterogeneous in size (0.1-1 μm), microparticles are small membrane vesicles released from activated and/or apoptotic cells. Although described since 1967 by Wolf [1], it is only since the 1990’s that microparticles have been considered as biomarkers as well as potential mediators of biological messages between cells [2] by acting as paracrine and endocrine vectors. Detection of microparticles has been performed in biological fluids (blood, synovial fluid, saliva for instance) and some solid tissues but also from the culture medium [3]. Levels of circulating microparticles are enhanced in a large number of pathological states including cardiovascular and metabolic disorders associated with insulin resistance and this has been linked to deleterious effects on cells from the vascular wall, mainly, endothelial cells. This review highlights the increasing impact of microparticles in major cardiovascular pathological situations associated with metabolic derangements.

The prevalence of obesity increases and is associated with increases in co-morbidities e.g. type 2 diabetes, hyperlipidemia, hypertension, obstructive sleep apnea, heart disease, stroke, asthma, several forms of cancer, depression, and may result in reduction of expected remaining lifespan. We have reviewed the adverse effects on the cardiovascular system of anti-obesity drugs now retracted from the market as well as the cardiovascular profile of current drugs and potential pathways which are considered for treatment of obesity. Fenfluramine, and sibutramine were withdrawn due to increased cardiovascular risk, while an inverse agonist at cannabinoid type 1 (CB1) receptors, rimonobant was withdrawn due to serious psychiatric problems. At present there are only few treatments available including orlistat and, phentermine alone or in combination with topiramate and lorcaserin, although cardiovascular side effects need to be clarified regarding phentermine and lorcaserin. Drugs approved for type 2 diabetes including glucagon like peptide (GLP-1) analogues and metformin also cause moderate weight losses and have a favourable cardiovascular profile, while the anti-obesity potential of nebivolol remains unexplored. Pathways with anti-obesity potential include sirtuin activation, blockade of transient receptor potential (TRPV1) channels, acetyl-CoA carboxylase 1 and 2 inhibitors, uncoupling protein activators, bile acids, crotonins, CB1 antagonists, but the cardiovascular profile remains to be investigated. For type 2 diabetes, new drug classes with possible advantageous cardiovascular profiles, e.g. GLP-1 analogues and sodium-glucose co-transport type 2 inhibitors, are associated with weight loss and are currently being evaluated as anti-obesity drugs.

Background: There is no widely accepted treatment for non-alcoholic fatty liver disease (NAFLD) or its advanced form, non-alcoholic steatohepatitis (NASH). Methods: We administered rosuvastatin (10 mg/day) for 1 year in patients with metabolic syndrome (MetS), NASH on liver biopsy and dyslipidaemia (but without diabetes or arterial hypertension). Patients also received lifestyle advice. Results: We report preliminary results for 6 patients. The second biopsy (at the end of the study) showed complete resolution of NASH in 5 patients, while the 6th, which had no improvement, developed arterial hypertension and substantial rise in triglyceride levels during the study. We suspect alcohol abuse despite advice to abstain. Serum alanine transaminase (ALT) and aspartate transaminase (AST) activities were reduced by 76 and 61%, respectively (p < 0.001 for both), during treatment, while γ-glutamyl transpeptidase (γ-GT), and alkaline phosphatase (AP) showed smaller non significant reductions. Fasting plasma glucose and glycated haemoglobin (HbA1c) were significantly reduced (p<0.05). Lipid values were totally normalised and liver ultrasonography showed a complete resolution of NASH in 5 patients. Body mass index and waist circumference remained unchanged during the study. Thus, changes in liver pathology and function should be attributed to treatment with rosuvastatin. A substantial limitation of the study is the small number of patients. Conclusions: These preliminary findings suggest that rosuvastatin could ameliorate NASH within a year of treatment in MetS patients with dyslipidaemia.

Patients with nephrotic syndrome are at increased risk for thromboembolic events such as deep venous and arterial thrombosis, renal vein thrombosis and pulmonary embolism. This thrombophilic phenomenon has been attributed to a “hypercoagulable” state in which an imbalance between naturally occurring pro-coagulant/pro-thrombotic factors and anti-coagulant/antithrombotic factors promotes in situ thrombosis in deep veins or arteries. Management of thromboembolic events may be divided in prophylactic and therapeutic strategies. Hypoalbuminemia is the most significant independent predictor factor of thrombotic risk, especially for values <2 g/dL. However, the most important question in these patients is whether to anticoagulate prophylactically or not. The decision depends on type of glomerulonephritis, proteinuria severity, other predisposing factors and prior history of thrombosis. Reviewing the recent literature, we suggest the best therapeutic management of anticoagulation for patients with nephrotic syndrome, focusing on prophylactic strategies.

The impact on cardiovascular events achieved by statin therapy seems to be mostly attributable to their cholesterol- lowering effect, with a highly debated contribution of the lipid-independent pleiotropic effects. Statins have an established role in the treatment of hypercholesterolemia with a clear and robust reduction in cardiovascular morbidity and mortality. Nevertheless, the pathophysiologic effect of statins on inflammatory responses and local atherosclerotic plaque morphology in humans remains a matter of debate. In particular, the question remains whether statin-induced alterations in plaque composition can be ascribed mainly to low density lipoprotein cholesterol (LDL-C) lowering or an antiinflammatory pleiotropic effect, or both. This review summarizes the available evidence of the effects of statins on carotid plaque cellular composition in clinical settings, focusing on lipid-related and lipid-independent effects of statin therapy. A systematic review of the web online databases was performed. Studies in humans evaluating the effect of statins on composition of carotid plaque removed at endarterectomy were eligible for inclusion. Data support the view that plaque composition even after a short-term lipid lowering therapy is significantly modulated by the degree of LDL-C lowering. A contribution of LDL-C independent, anti-inflammatory mechanisms of statins on plaque stability is only suggested by some of the studies. Actually, data strongly support the current guidelines based on progressively lower LDL-C targets depending upon the cardiovascular risk of individual patients.

Non-dipping is a common pattern of arterial hypertension and it is associated with increased cardiovascular risk. Use of ambulatory blood pressure monitoring, as suggested in recent guidelines, could further increase its prevalence among subjects with hypertension. In this review we discuss assessment, relevance and associated factors. Non-dipping could be addressed through chronotherapy, the use of specific classes of anti-hypertensives, such as renin-angiotensin blockers, or modification of associated factors. However, more data are needed in order to comprehensively estimate factors associated with non-dipping and how they could be modified.