Current Vascular Pharmacology - Volume 11, Issue 6, 2013

Stroke is the second cause of death worldwide and one of the leading cause of disability. Due to the high rate of recurrence, in high risk-patients (eg patients affected by atherosclerotic vascular disease), long-term antiplatelet therapy reduces the risk of vascular events such as non-fatal myocardial infarction, non-fatal stroke, or vascular death. The percentage of reduction of the events can be estimated in approximately 25%. These data justify the directions that are given to us by the current guidelines for prevention of secondary stroke, which recommend the broad use of antiplatelet therapy both for the secondary prevention of stroke in patients with a history of non-cardioembolic stroke or TIA. As for the primary prevention indications are less accurate because the absolute benefi ts of aspirin in reducing the happening of vascular events, are generally much lower than in secondary prevention. Although several trials have been investigated use of antiplatelet drugs in ischemic stroke patients, ascertaining the sure benefit, especially in secondary prevention in non-cardioembolic stroke, various issues remains unclarified, and new questions raises with the analysis of the results of available trials.

Statin is now recommended in secondary prevention after stroke or transient ischemic attacks to reduce the risk of a new stroke or major cardiovascular events. However, some issues about the extent of the benefit in some stroke patients and the risk of cerebral hemorrhage remain debated. This review shows that statins are significantly effective in decreasing the risk of further strokes despite an increase in the risk of brain hemorrhage. A significant benefit was observed in men and women, in aged patients and possibly to a greater extent in patients with carotid artery stenosis. Intensive statin therapy lowering the LDL-cholesterol beyond the cut-off value of 1.8 mmol/L (70 mg/dl) seems to be more effective than less intensive treatment and without an increased risk of side effects. Overall, statins are well tolerated. Further prospective studies should clarify whether the effect is of the same magnitude in small vessel disease and how to select the patients to reduce the risk of cerebral hemorrhage.

Among the different subtypes of ischaemic strokes, almost 20 % are of cardiac origin. Different are the causes of cardioembolic stroke, but the most common is the atrial fibrillation, a supraventricular arrhythmia. Appropriate use of antiplatelet drugs and anticoagulants after transient ischaemic attack (TIA) or ischaemic stroke depends on whether the underlying cause is cardioembolic or of presumed arterial origin. Adequate antiplatelet therapy is recommended for secondary prevention after cerebral ischaemia of presumed arterial origin, whether for patients with TIA and ischaemic stroke of cardiac origin, mainly due to atrial fibrillation. Vitamin K antagonists (VKAs) are highly effective in preventing recurrent ischaemic stroke but have important limitations and are thus underused. Current guidelines still regard Vitamin K Antagonists at INR 2·0–3·0 to be the standard treatment after cerebral ischaemia of cardiac origin for patients who can tolerate them. In this setting antiplatelet therapy provides an alternative when oral anticoagulation is contraindicated or when patient choice or compliance limits choice of therapy, but is much less effective than VKAs. Recent trial data performed with new anticogulants such as the factor Xa and thrombin inhibitors will need to be taken into account, in order to prevent several of the clinical problems actually related to VKAs use.

Thrombotic strokes can affect large or small arteries in the brain. Drugs to prevent atherosclerosis complication such as thrombotic strokes, should be drugs able to prevent the accumulation of intravascular fat, reduce vascular proliferation, decrease blood pressure levels with the resulting shear stress, reduce platelet aggregation, and possibly partially or totally reverse carotid plaques. Any of the commonly used antihypertensive drugs lower the incidence of stroke, with larger reductions in BP resulting in larger reductions in risk. Experimental and clinical data suggest that reducing the activity of the renin-angiotensin aldosterone system (RAAS) may have beneficial effects beyond the lowering of blood pressure to reduce stroke incidence. In clinical trials, statins consistently reduced the risk of ischemic stroke in patients with or without CHD whereas the data on the effects of other lipid modifying drugs on stroke risk are limited. Approximately 25% of strokes are recurrent. Antiplatelet therapy is indicated for the prevention of recurrent stroke in patients with a history of noncardioembolic minor stroke or transient ischemic attack (TIA). Although clinicians may choose acetylsalicylic acid (ASA) as first-line therapy for secondary prevention, clinical guidelines and evidence from trials suggest that ASA may not be the most effective strategy. A recent review discussed results from clinical trials that have compared the efficacy of ASA monotherapy versus ASA + extended release dipyridamole in secondary stroke prevention. Therefore it is difficult to extrapolate the real benefit of pharmacological prevention strategies against atherothrombotic subtype for excellence in the TOAST classification subtype that is represented by the LAAS and also with regard to lacunar subtype as an expression of lipohyalinosis process which is a further aspect of atherosclerosis.

The metabolic syndrome (MetS) is a complex multifactorial disorder and its incidence is on the increase worldwide. Due to the definitive link between obesity and the MetS weight loss strategies are of prime importance in halting the spread of MetS. Numerous epidemiological studies provide evidence linking dietary patterns to incidence of MetS symptoms. As a consequence of the epidemiology studies, dietary intervention studies which analyse the effects of supplementing diets with particular nutrients of interest on the symptoms of the MetS have been conducted. Evidence has shown that lifestyle intervention comprising changes in dietary intake and physical activity leads to an improved metabolic profile both in the presence or absence of weight loss thus highlighting the importance of a multi-faceted approach in combating MetS. Nutritional therapy research is not focused solely on reducing energy intake and manipulating macronutrient intake but is investigating the role of functional foods or bioactive components of food. Such bioactives which target weight maintenance and /or insulin sensitivity may have a potentially positive effect on the symptoms of the MetS. However the efficacy of different functional nutrients needs to be further defined and clearly demonstrated.

The metabolic syndrome (MetS) is a cluster of metabolic conditions associated to abdominal obesity, such as elevated blood pressure, impaired glucose tolerance, insulin resistance, elevated triglycerides, and low high-density lipoprotein cholesterol concentrations. Each of the associated conditions has an independent effect, but clustering together they become synergistic, making the risk of developing cardiovascular disease (CVD) greater. There is a big debate as to whether the MetS alone or its associated health conditions are more important for CVD incidence and mortality or whether prevention and/or treatment of the MetS will reduce CVD incidence and mortality. This article reviews the evidence that demonstrates that individuals with the MetS are at increased risk for CVD incidence and mortality and discusses these debated issues.

Metabolic syndrome (MetS) is associated with increased risk of both atherothrombotic cardiovascular events and venous thromboembolism. The pro-thrombotic potential of MetS, may explain this association. In this review we discuss the relationship of MetS with hemostasis focusing on endothelial function, platelet activity, coagulation, fibrinolysis and hemorheologic markers. Endothelial-dependent vasodilatation is impaired in MetS. This is mostly mediated by a reduced expression of vasodilators (nitric oxide and prostacyclin) with a concomitant increase of vasoconstrictors (endothelin- 1, angiotensin II and thromboxane A2). Platelet activity is enhanced in MetS. A cross-talk between activated endothelium and platelets results in a pro-thrombotic vicious cycle. Enhanced coagulation together with impaired fibrinolysis is also present in MetS. This is mirrored by high fibrinogen and plasminogen activator inhibitor-1 levels. Endothelial dysfunction, expressed by high von Willebrand factor and tissue plasminogen factor levels, also contributes to this abnormality. Whole blood and plasma viscosity is increased in MetS. Lifestyle intervention can improve the MetS-related pro-thrombotic state. These measures include weight reduction and improved composition of the diet. A Mediterranean-style diet rich in olive oil, as a source of monounsaturated fat, and low saturated fat consumption may also be beneficial.

The metabolic syndrome (MetS) is a cluster of risk factors for the development of cardiovascular disease and type 2 diabetes mellitus. These risk factors include raised blood pressure, dyslipidemia (raised triglycerides and lowered high-density lipoprotein cholesterol), raised fasting glucose, and central obesity. MetS has become a serious public health and clinical problem whose prevalence and incidence are increasing along with the worldwide rise in rates of obesity and sedentary lifestyles. A number of studies have shown that MetS is associated with a state of low-grade inflammation, characterized by abnormal pro-inflammatory cytokine production, increased acute-phase reactants, and activation of a network of inflammatory signalling pathways. Moreover, MetS has also been linked to oxidative stress, a consequence of a reduction in the antioxidant systems and an increase in the production of reactive oxygen species. Nevertheless, agreement exists that dietary intervention may modulate the pro-inflammatory state and lessen oxidative stress related to MetS, thereby decreasing the cardiovascular risk. In this review we address the current available evidence regarding dietary modulation of inflammation and oxidative stress associated with MetS.

Metabolic Syndrome (MetS) is a complex disorder defined by the aggregation of interconnected cardiometabolic risk factors which increase the risk of diabetes mellitus type 2 and cardiovascular disease (CVD). MetS is currently a matter of concern and it will continue to be in the future, since there is likely to be a dramatic increase in its prevalence, and subjects with MetS will have an increased risk of mortality, mainly through CVD. Moreover, the implications on the global health burden and the worldwide epidemic of this complex disorder will impact greatly on socioeconomic cost. MetS is therefore a matter of serious concern and we need to understand its etiology in order to improve strategies of treatment and prevention. In this regard, postprandial lipemia has increased in importance over the last few years as it has been demonstrated to influence the development of atherosclerosis. In addition, in modern times, fasting is not the typical physiological state of humans; in fact, they spend most of the time in the postprandial state. However, although it is obvious that postprandial lipemia is present in conditions of obesity, little is known about the relevance of postprandial lipemia in MetS. In the current review, we will explore some aspects of postprandial lipemia which could be of interest for understanding the pathogenesis of this complex disorder and which may help us advance towards more personalized nutrition.

Diet and lifestyle are major modifiable determinants of inflammation, hypertension, atherogenic dyslipidemia, glucose metabolism and central obesity and should be targeted for the prevention and treatment of the metabolic syndrome. As insulin resistance, raised fasting and postprandial insulin levels, impaired carbohydrate tolerance and, ultimately, diabetes (all components of the metabolic syndrome) have been related to increased cardiovascular risk, in this report we review the potential role that individual nutrients, foods/food groups, and dietary patterns play in insulin sensitivity and secretion in the management of metabolic syndrome. We also discuss the effect of diet alone on inflammation and the homeostatic control of glucose, regardless of the effect of exercise and weight loss.

The metabolic syndrome (MetS) is a constellation of metabolic risk factors reflecting overnutrition and sedentary lifestyle and its increasing prevalence is reaching epidemic proportions. The importance of MetS lies in its close association with the risk of cardiometabolic disease. In this scenario, the principal goals of pharmacological therapy for these patients are to achieve and maintain an optimal cardiometabolic control, including lipids, blood glucose and blood pressure; in order to prevent and treat potential complications. Moreover nutrition has commonly been accepted as a cornerstone of treatment for MetS, with the expectation that an appropriate intake of energy and nutrients will improve its control. However the question arises as to whether dietary therapy may require a more personalised approach. In this regard improvements in genetic analysis have enhanced our understanding of the role of genetics in this dietrelated condition. In this review we will present recent data highlighting the importance of gene-nutrient interactions in the context of MetS risk.

Obesity is dramatically increasing virtually worldwide, which has been linked to the rising prevalence of metabolic syndrome. Excess fat accumulation causes severe alterations in adipose tissue function. Actually, adipose tissue is now recognized as a major endocrine and secretory organ that releases a wide variety of signaling molecules (hormones, growth factors, cytokines, chemokines, etc.), the adipokines, which play central roles in the regulation of energy metabolism and homeostasis, immunity and inflammation. In addition, adipose tissue is no longer regarded as a passive lipid storage site but as a highly dynamic energy depot which stores excess energy during periods of positive energy balance and mobilizes it in periods of nutrient deficiency in a tightly regulated manner. Altered lipid release and adipokine production and signaling, as occurs in obesity, are linked to insulin resistance and the associated comorbidities of metabolic syndrome (dyslipidemia, hypertension), which confer an increased risk for the development of type 2 diabetes and cardiovascular disease. Here we summarize current knowledge on adipose tissue and review the contribution of novel techniques and experimental approaches in adipobiology to the identification of novel biomarkers and potential targets for dietary or pharmacological intervention to prevent and treat adipose tissue-associated diseases.

Vitamin D is essential in bone mineralization and calcium homeostasis, and an increasing body of evidence suggests that vitamin D may be important for maintaining extraskeletal health, including having beneficial effects on cardiometabolic outcomes. Vitamin D deficiency is widespread, but the role of vitamin D in the metabolic syndrome is not fully elucidated. In this review we summarize data from observational studies and randomized controlled trials on the relation between vitamin D and the metabolic syndrome and its components. A large number of observational studies suggest a relationship between low levels of 25(OH)D and the metabolic syndrome or its individual clinical features. Randomized controlled trials of vitamin D supplementation addressing aspects of the metabolic syndrome have yielded inconsistent results, and many studies suffer from methodological limitations. There is an urgent need for large, well-designed randomized controlled trials with relevant endpoints. Until definitive results from such studies are available, caution should be taken towards the use of vitamin D-supplementation for disorders other than musculoskeletal system. New molecular biological techniques elucidating the interaction between the active vitamin D derivatives and target genes represent a promising approach to more precise knowledge about new biomedical function, which also might shed light on the complex metabolic syndrome.

Background/Objective: Ranolazine is a new anti-ischemic agent approved for chronic angina with additional electrophysiologic properties. The purpose of the present trial was to investigate its effect in preventing postoperative atrial fibrillation (POAF) after on-pump coronary artery bypass graft (CABG) surgery. Methods: In the current prospective, randomized, (1 active: 2 control), single-blind (outcome assessors), single-centre clinical trial we recruited consecutive eligible patients scheduled for elective on-pump CABG. Participants were assigned to receive either oral ranolazine 375 mg twice daily for 3 days prior to surgery and until discharge, or to receive usual care. Patients were monitored for the development of POAF. Results: We enrolled 102 patients. Significantly lower incidence of POAF was noted in the ranolazine group compared with the control group (3 out of 34 patients, 8.8%, vs 21 out of 68 patients, 30.8%; p< 0.001). Mean values of left atrial diameter and left ventricular ejection fraction between the control and the ranolazine group were not significantly different. Conclusion: Our findings suggest a protective role of oral ranolazine when administered in a moderate dose preoperatively in patients undergoing on-pump CABG surgery. Future studies based on a wider sample of patients will eventually support our conclusions.

Objective: The use of dipeptidyl-peptidase 4 (DPP4) inhibitors and glucagon like peptide 1 (GLP1) analogues for the treatment of diabetic mellitus (DM) type 2 is growing. Currently some of these agents have been approved in combination with insulin. Methods: We considered randomised controlled trials (RCTs) evaluating GLP1 analogues or DDP4 inhibitors combined with basal insulin in diabetic patients. We were limited to trials published in English language. Results: PubMed search retrieved 207 items. After excluding irrelevant items we ended with 7 eligible studies with 1808 participants. Mean baseline HbA1c was 8.5% and median follow up was 24 weeks. Exenatide combined with insulin was used in 2 studies; DPP4 inhibitors were used in 5 studies (2 with sitagliptin, 1 with saxagliptin, 1 with vildagliptin and 1 with alogliptin). Conclusion: Incretin-based therapies combined with basal insulin are able to reduce HbA1c by 0.5-0.7%. DPP4 inhibitors have no significant effect on weight, whereas GLP1 analogues reduced weight by 1-2 kg. Hypoglycaemia rates were generally comparable in all treatment groups. These are promising results, but the available evidence is limited. This is a poorly investigated field with few RCTs. New studies focusing on head-to-head comparisons with short-acting insulin on top of basal insulin are needed.

Background: Acute kidney injury (AKI) develops in 10% of patients after surgical abdominal aortic aneurysm (AAA) repair. Neutrophil gelatinase-associated lipocalin (NGAL) is a predictor of AKI and Endothelial Progenitor Cells (EPCs) represent a potential repair mechanism for vascular lesions. We evaluated the diagnostic power of serum (s) and urine (u) NGAL in detecting a possible event of AKI in patients undergoing surgical treatment for AAA repair. We also investigated the influence of vascular injury on EPCs. Methods: We examined 50 patients who underwent open AAA repair. Blood and urine was collected preoperatively and every hour after surgery until 8 h to quantify sNGAL, uNGAL and circulating EPCs. AKI, was defined as a 25% decrease in eGFR compared with baseline values. Results: There was an inverse correlation between eGFR, sNGAL and uNGAL, while a direct correlation between sNGAL APACHE II Score and EPCs was found. At receiver operating characteristic (ROC) analysis, sNGAL and uNGAL showed a very good diagnostic profile. Kaplan Meier curves showed that NGAL is a highly sensitive predictor of incidence of AKI. Univariate followed by multivariate Cox proportional hazard regression analysis showed that uNGAL and sNGAL predicted AKI independently of other potential confounders, including eGFR and APACHE II Score. Patients had at baseline and after surgical stress a significantly higher number of EPCs than control group. Conclusions: NGAL represents an independent renal predictor of incidence of AKI. EPCs reflect the degree of vascular damage and could be considered as an indicator of disease with a reparative-regenerative vascular-endothelial function.