Current Vascular Pharmacology - Volume 13, Issue 2, 2015

The primary cause of cerebrovascular disease is atherosclerosis, to which many factors contribute. At first many saw atherosclerosis as a lipid-driven disease. Recently inflammation has appeared as a significant factor in the disease. Innate immune cells, for example monocytes and macrophages, are important in atherosclerosis. Toll-like receptors (TLRs) are the best-studied family of receptor in the immune system. TLR engagement with their ligands stimulates pro-inflammatory cytokine production and foam cell generation. Recently certain TLRs have shown a protective role in atherosclerosis. In this review, we analyse innate immunity, focusing on TLR signalling and macrophages, in atherosclerosis and acute cerebrovascular complications, and thereby discuss their potential as therapeutic targets.

Matrix metalloproteinases (MMP) comprise a family of at least 25 zinc-dependent endopeptidases that play a pivotal role in the physiopathology of the mammalian central nervous system. In the first phases after stroke, the dysregulation of MMPs has been described to increase acute neurovascular disruption and cerebral injury. In particular, MMP-mediated alterations lead to blood-brain barrier (BBB) leakage, cerebral edema, hemorrhage, leukocyte infiltration and progressive inflammatory reactions underlying brain tissue loss. In addition, MMPs have been also shown to play critical activities during the repair phases of cerebral ischemia, particularly during angiogenesis and reestablishment of cerebral blood flow. The aim of this narrative review is to elucidate the mechanisms by which MMPs may provide detrimental and/or beneficial effects during the post-stroke injury and repair phases in animal models.

During the last decades, the improvements in the assessment and management of cardiovascular risk have been successful in the reduction of acute cardiovascular outcomes. Among different prevention and therapeutic strategies, treatments targeting HDL increase have been indicated as promising interventions from both basic research and clinical studies. Although this therapeutic approach still requires confirmatory findings from large clinical trials, emerging evidence indicates that it would be particularly useful in some patient categories characterized by accelerated atherosclerotic diseases. In this regard, HIV-infected patients (under antiretroviral treatment or not) have been recently indicated as an appropriate target population. The present review will discuss the promising role of HDL in HIV-related cardiovascular pathophysiology and update novelties from clinical studies targeting HDL increase in HIV patients.

Stroke, a leading cause of death or disability worldwide, is frequently dependent on the rupture of carotid atherosclerotic plaques. It is therefore extremely important to study the mechanisms of formation, progression and eventually rupture of the plaques. Vulnerability of the plaque, the intrinsic tendency to lose its integrity and consequently to induce a dramatic atherothrombotic or embolic event, is still an elusive concept because many players are involved and the clinical picture is frequently the sum of different contrasting (pro-inflammatory and anti-inflammatory) phenomena. This review will discuss recent advancements in the comprehension of this topic. In particular inflammatory activation at the level of the carotid plaque will be described in the attempt to underline the main factors for the formation, the chronic persistence and the risk of rupture. Since these topics can be studied in humans only with plaque samples obtained following endarterectomy, research has tried to evaluate the role of different biomarkers which could be useful for the definition of the vulnerability of a carotid plaque, or, with more clinical relevance, of a patient; some recent results from our group will be discussed. A significant help for clinical decisions may also come from imaging tools, both well established ultrasound and more sophisticated options, such as magnetic resonance and positron emission tomography. This large amount of scientific information should allow the development of new therapeutic approaches for the effective prevention of cerebrovascular events.

Plaque vulnerability due to inflammation has been shown to be a participating factor in the degenerative process in the arterial wall that contributes to stenosis and embolism. This is believed to have an important role to play also in the genesis of stroke or cerebrovascular diseases. In order to appropriately screen patients for treatment, there is an absolute need to directly or indirectly visualize both the normal carotid and the suspected plaque. This can be done with a variety of techniques ranging from ultrasound to computed tomography (CT) and magnetic resonance imaging (MRI). In addition to angiographic techniques, direct imaging of the plaque can be done either by ultrasound or by the so-called molecular imaging techniques, i.e. positron emission tomography (PET). These findings, together with other clinical and paraclinical parameters should finally guide the therapeutic choice.

Inflammation, endothelial dysfunction, and platelet activation contribute to the prothrombotic pro-inflammatory state associated with AF. Inflammatory biomarkers, such as C-reactive protein and interleukin 6, promote the production of tissue factor (TF) and von Willebrand factor (vWF) and aggravate endothelial dysfunction leading to increased coagulation and depressed fibrinolytic activity. The interaction of vWF and glycoprotein Ib (vWF-GPIb) receptor activates 'thrombo-inflammatory' pathways promoting thromboembolism. Moreover, platelet activation driven by plateletleukocyte/ monocyte interaction attribute to AF-related thrombosis. Biochemical pathways such as CD40-CD40 ligand and P-selectin-P-selectin glycoprotein ligand 1 are considered important mediators of platelet-leukocyte interactions in the setting of AF. Further studies are required to address the clinical implications of inflammatory biomarkers in the prediction of AF-related thromboembolism. Indeed, inflammatory pathways could be also considered as therapeutic targets in an effort to reduce the clinical consequences of thromboembolism and improve outcomes in AF.

Dyslipidemia represents one of the major risk factors for atherosclerosis affecting the arteries of large and medium caliber and consequently causing ischemia in the brain, heart, or legs. Coronary artery disease and cerebral stroke represent the major causes of morbidity and mortality among the elderly and middle aged subjects. The change of lifestyle can reduce the risk of cardiovascular disease but available drug therapy (in particular statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase) is effective in modifying hyperlipidemia and consequently reducing cardiovascular events. The hypolipemic drugs can prevent, slow the progression and sometimes determine the regression of atherosclerotic plaques, therefore significantly reducing the clinical complications of atherosclerotic cardiovascular disease. In this review, we want to point out the role of the different lipoproteins, such as triglycerides, HDL-C, LDLC, Lp(a), in the pathogenesis of stroke and the role of statins in reducing both lipid fractions and stroke risk.

Hypoxia, a condition of insufficient oxygen availability to support metabolism, occurs when the vascular supply is interrupted, as in stroke. The identification of the hypoxic and viable tissue in stroke as compared with irreversible lesions (necrosis) has relevant implications for the treatment of ischemic stroke. Traditionally, imaging by positron emission tomography (PET), using 15O-based radiotracers, allowed the measurement of perfusion and oxygen extraction in stroke, providing important insights in its pathophysiology. However, these multitracer evaluations are of limited applicability in clinical settings. More recently, specific tracers have been developed, which accumulate with an inverse relationship to oxygen concentration and thus allow visualizing the hypoxic tissue non invasively. These belong to two main groups: nitroimidazoles, and among these the 18F-Fluoroimidazole (18F-FMISO) is the most widely used, and the copper-based tracers, represented mainly by Cu-ATSM. While these tracers have been at first developed and tested in order to image hypoxia in tumors, they have also shown promising results in stroke models and preliminary clinical studies in patients with cardiovascular disorders, allowing the detection of hypoxic tissue and the prediction of the extent of subsequent ischemia and clinical outcome. These tracers have therefore the potential to select an appropriate subgroup of patients who could benefit from a hypoxia-directed treatment and provide prognosis relevant imaging. The molecular imaging of hypoxia made important progress over the last decade and has a potential for integration into the diagnostic and therapeutic workup of patients with ischemic stroke.

Neuroinflammation is a complex biological response to any injury occurring to the central nervous system. It is mainly characterized by the recruitment of immune system cells, namely the microglial cells, in the site of injury. Once activated, microglia expresses a cholesterol transporter protein (TSPO), previously also known as peripheral type benzodiazepine receptor. PK11195 is a ligand for TSPO and, labelled with a positron emitter, it is also the most used tracer for PET molecular imaging to in vivo map the microglia activation in various neurological disorders, including ischemic stroke. Recent [11C]PK11195 PET studies proved activated microglia both locally in the area of the infarct and at distance along the affected fibre tracts, suggesting the presence of two different microglia subtypes with peculiar functions in disease progression. The aim of this review is to discuss the most recent knowledge about imaging neuroinflammation in ischemic stroke and in the atherosclerotic and vascular inflammatory disorders, trying to elucidate the interplay between the clinical course and the activation of a microglial response.

Prospective observational studies have shown that arterial stiffness is a strong and independent predictor of cardiovascular disease in hemodialysis patients. Recent evidence further supports that arterial hardening predicts cardiovascular and all-cause mortality in peritoneal dialysis patients, renal transplant recipients and patients with chronic kidney disease (CKD) not on dialysis. Of note, dissociation of arterial stiffness with blood pressure reduction were related to worsened cardiovascular outcome in kidney disease patients, suggesting that arterial stiffness may not only be a predictor, but also a true risk factor, representing a specific and potentially reversible pattern of outward arterial remodeling in these individuals. On this basis, arterial stiffness has emerged as a novel therapeutic target for cardiovascular risk reduction in patients with CKD; specific interventions, such as renin-angiotensin-system blockade, use of statins, and decrease of calcium- phosphate product may delay the progression of arteriosclerotic process. This article summarizes the accumulated evidence from clinical and epidemiological studies regarding the prognostic significance of arterial stiffening on cardiovascular outcomes and provides insights on possible treatment strategies for arterial stiffness attenuation in patients with CKD.

Objective: To evaluate the impact of statins on carotid restenosis (CR) >50% and future cardiovascular events (CVE), in patients undergoing carotid endarterectomy (CEA). Methods: 570 consecutive patients (656 CEAs) operated between 1990 and 2009, were included in this retrospective study. The study cohort was followed for an average of 82 months (median 80, range 12- 180 months). Endpoints were the development of CR >50%, the occurrence of CVE (myocardial infarction, stroke) and overall mortality. Kaplan-Meier curves and Cox regression models were used to assess outcomes. Results: 92 restenosis events were recorded. Freedom from restenosis >50% at 5, 10 and 15 years of follow-up was 92, 82 and 69%, respectively. Compared with statin-receivers, statin-free patients had a significantly higher 15-year restenosis rate (41 vs 10%; P = .001), a significantly higher CVE rate (49 vs 14%; P = .001) and a significantly higher mortality rate (24 vs 18%; P = .034). Adjusting for other covariates statins were independently associated with lower restenosis rate (hazard ratio [HR], 0.52; 95% CI, 0.31-0.88; P= .016), cardiovascular events (HR, 0.40; 95% CI, 0.26-0.61; P < 0.001) and long-term mortality (HR, 0.56; 95% CI, 0.33-0.95; P = .032). Conclusion: Statins not only reduce cardiovascular events and mortality but may also have an important effect on the anatomic durability of CEA. These data support the use of statins in patients with carotid stenosis undergoing CEA.

Warfarin inhibits vitamin-K dependent proteins involved in bone mineralization and the prevention of vascular calcification (bone Gla protein BGP, matrix Gla protein MGP). In this multicenter, cross-sectional study with 3-year follow-up, data from 387 patients on hemodialysis for ≥1 year at 18 dialysis units were analyzed. Patients on warfarin treatment for > 1 year (11.9% of the population) were compared with the remaining cohort for vertebral fractures, vascular calcifications and mortality. Vertebral fractures and vascular calcifications were sought in L-L vertebral X-rays (D5 to L4). Compared with controls, warfarin-treated male patients had more vertebral fractures (77.8 vs. 57.7%, p<0.04), but not females (42.1% vs. 48.4%, p=0.6); total BGP was significantly reduced (82.35 vs. 202 μg/L, p<0.0001), with lower levels in treated men (69.5 vs. women 117.0 μg/L, p=0.03). In multivariate logistic regression analyses, the use of warfarin was associated with increased odds of aortic (OR 2.58, p<0.001) and iliac calcifications (OR 2.86, p<0.001); identified confounders were age, atrial fibrillation, angina, PPI use and total BGP. Seventy-seven patients died during a 2.7±0.5 year follow-up. In univariate Cox regression analysis, patients on warfarin had a higher risk of all-cause mortality (HR 2.42, 95% CI 1.42-4.16, p=0.001) when compared with those untreated and data adjustment for confounders attenuated but confirmed the significant warfarin-mortality link (HR: 1.97, 95% CI: 1.02-3.84, P=0.046). In hemodialysis patients, additional studies are warranted to verify the risk/benefit ratio of warfarin, which appears to be associated with significant morbidity and increased mortality.

Objective: Soluble receptor for advanced glycation end products (sRAGE) levels have been found to be decreased in chronic inflammatory diseases including atherosclerosis, hypertension and renal failure. This study evaluated the relationship between sRAGE concentrations and urinary albumin excretion in patients with essential hypertension. Methods: A total of 200 consecutive patients with essential hypertension were enrolled and were divided into 3 groups. Results: Plasma sRAGE levels were significantly lower in hypertensive patients with micro- or macroalbuminuria compared with those in hypertensive patients with normoalbuminuria, and the values in the macroalbuminuria group were even lower than in the microalbuminuria group (128.6±24.2, 244.6±37.6,313.6±30.7 pg/ml, respectively). In addition, plasma sRAGE level was an independent determinant of log urinary albumin excretion in patients with essential hypertension (β=-0.267, P<0.05). Conclusions: sRAGE may play a role in the pathogenic processes that link albuminuria, chronic inflammation and oxidative stress in hypertensive patients.

Background: Kallistatin (KS) is a serine proteinase. The result of KS on ‘Renal Ischemia- Reperfusion Injury’ (IRI) has not clearly been researched. In this study, investigative research has been conducted to draw results on the administration of human KS on kidney response conducted within a mouse model of IRI. Materials and Methods: BALB/c mice were used and given 30 min ischemia that was injected into the kidney which was followed with 24 h reperfusion. The human KS gene contained within an adenoviral vector was injected intravenously 30 min before reperfusion and 12h after reperfusion. Analyses illustrated what impact KS had on renal IRI in realtion to tubular necrosis, apoptotic cell death, inflammatory cytokines, renal function, and inflammatory cell infiltration. Results: KS gene transfer significantly had a positive impact on renal function (reduced blood urea-nitrogen: 73.5±13.6 vs. 195.4±14.6 mg/dL at day three, p < 0.05 and the serum creatinine levels: 0.23±0.02 vs. 0.71±0.14 mg/dL at day three, p < 0.05), reduced tubular necrosis and apoptosis of IRI kidneys. The permeation of cells that were inflamed and the manufacturing of pro-inflammatory cytokines (RANTES-is regulated through been activated with normal T-cell which are expressed and secreted, tumour necrosis interleukin-1β factor-α, and interferon-γ) resulted in significantly suppressing KS in mice with IRI. The efficacy to scavenge superoxide in tubule cells was also demonstrated by high-performance liquid chromatography. Conclusion: Our study suggests a novel role of KS in renal protection after ‘Renal Ischemia-Reperfusion Injury’ blocking of oxidative stress and renal inflammation.