Current Vascular Pharmacology - Volume 11, Issue 3, 2013

Antimicrobial treatment to attenuate expansion of abdominal aortic aneurysm has been suggested, especially with the focus on Chlamydophila. In this systematic literature review only four randomized trials were identified. In two small studies there is an indication of an effect of roxithromycin. In conclusion, however, more studies are needed, and they must be properly sized based on power calculations as well as antimicrobially relevant. Such trials are on the way both in Europe and the US, the results being awaited with interest.

There is strong epidemiological evidence that patients with diabetes have a lower incidence of abdominal aortic aneurysm. The precise mechanism of this negative association is unknown. Whilst a number of studies have supported the hypothesis that protection is a function of diabetes-mediated changes in the vascular extracellular matrix biology, there is also support for the idea that the treatment regimens used in diabetes may afford protection against AAA. In particular the pleiotropic drug family, the thiazolidinediones have been examined as candidates to ameliorate aneurysm formation. Both the thiazolidinediones, and the structurally related family, fibrates, have been shown to have anti-inflammatory and antioxidative effects, in addition to ability to modulatate glucose and lipid homeostasis. In this brief review we present the current data exploring the use of thiazolidinediones in experimental aneurysm development. Despite the fact that both thiazolidinediones Rosiglitazone and Pioglitazone are no longer prescribed in Europe and the US, they have provided important insights into the mechanism of action, and the application of other pleiotropic drugs in the treatment of AAA. One such pleiotropic drug is high-density lipoproteins (HDLs), which have been shown to have a broad spectrum of effects, including activation of PPARs, which may favour their use as a new drug target for protection against AAA development.

Abdominal aortic aneurysm (AAA) is a significant health problem in the elderly. Efforts to limit the mortality rate depend on early detection and elective AAA repair. The benefit of early detection of AAAs, by ultrasound screening is limited since early repair of small AAA has been shown to provide no clinical advantage. There is currently no established pharmacotherapeutic treatment for small AAAs. In the first part of this review, we describe the potential mechanisms whereby statins can modulate the pathological processes associated to experimental and human AAA. Among them, statins are able to regulate leukocyte recruitment and immuno-inflammatory responses, platelet activation, oxidative stress, proteolysis and extracellular matrix breakdown. However, controversial results have been obtained in experimental models of AAA. In the second part of this review, we analyze the effect of statins in both, cardiovascular events on AAA patients and AAA growth. Although statin treatment is recommended for all AAA patients with the aim of reducing the incidence of cardiovascular events and death, controversial results have been shown between experimental and clinical studies regarding the potential preventive effect on AAA growth. One potential reason for these discrepancies could be related to the fact that statins reduce total cholesterol concentrations but do not modify HDL concentrations, the most sensitive predictor of AAA among lipid markers. In this respect, it could be of interest to test the effect of drugs modulating plasma HDL concentrations on AAA evolution.

The physiological transport in the aortic wall occurs mainly by centrifugal convection from the lumen to the adventitia through the arterial wall. Enlargement of an abdominal aortic aneurysm (AAA) is usually associated with the development of an intraluminal mural thrombus (ILT). The interface between the luminal side of the thrombus and flowing blood is a site of constant thrombus renewal, which is linked to platelet aggregation-induced fibrin generation and accumulation. In addition, red blood cells are entrapped causing an oxidative response. Through centrifugal convection are factors increasing the inflammatory and degenerative response transported from the ILT to media and adventitia. Two experimental studies on rats with experimental AAA have shown that aneurysmal progression can be impaired by antiplatelet agents. By a systematic literature search, 4 human cohorts were identified analysing the effect of antiplatelet treatment on the progression of AAA. The two largest cohorts couldn´t detect any significant difference. However, the cohorts included very small AAA, in which ILT seldom is present. In the two other trials, only testing AAA sized above 35 and 39 mm, respectively, use of low dose aspirin was associated with significantly lower expansion rates and less need for later surgical repair. Size-based subgroup analyses from relevant existing cohorts ought to be conducted for confirmation. Finally, low dose aspirin is recommend as general cardiovascular secondary prevention, however, large-scaled trials comparing low dose aspirin with more potent antiplatelets would be relevant.

Mast cells (MCs) are proinflammatory cells that play important roles in allergic responses, tumor growth, obesity, diabetes, atherosclerosis, and abdominal aortic aneurysm (AAA). Although the presence and function of MCs in atherosclerotic lesions have been thoroughly studied in human specimens, in primary cultured vascular cells, and in atherosclerosis in animals, their role in AAA was recognized only recently. Via multiple activation pathways, MCs release a spectrum of mediators — including histamine, inflammatory cytokines, chemokines, growth factors, proteoglycans, and proteases — to activate neighboring cells, degrade extracellular matrix proteins, process latent bioactive molecules, promote angiogenesis, recruit additional inflammatory cells, and stimulate vascular cell apoptosis. These activities associate closely with medial elastica breakdown, medial smooth-muscle cell loss and thinning, outer media and adventitia inflammation, aortic wall expansion, endothelium erosion, and eventual rupture and thrombosis. Experimental animal AAA models and MC reconstitution technique allowed examination of a direct role of MCs in AAA pathogenesis, and identification of the exact role of each MC-derived molecule. Genetic deficiency of MCs, pharmacological inhibition of MC degranulation, absence of MC-specific chymase and tryptase, or inhibition of these proteases, all effectively attenuated or abolished experimental AAA growth. The role of MCs have been reproduced in humans in several case-control studies, and two cohort studies showing the systemic level of MC specific chymase and tryptase is associated with aneurysmal growth rate, need for later aneurysmal repair and even overall mortality. These observations offer new opportunities to prevent or slow AAA growth in humans, and specific antimastcell drugs inhibiting degranulation of MCs have been used for especially allergic diseases for decades. It clearly calls for randomized clinical trials as no medical treatment to inhibit AAA progression so far have shown to be efficient.

Adenosine is an endogenous purine nucleoside that is an important metabolic sensing molecule. It is released during conditions of low oxygen delivery to tissues and organs to activate a range of effects in vascular tissues. Adenosine has a role in the vasculature by mediating vasodilation, vessel remodelling, cell proliferation as well as antiplatelet and inflammatory responses. Also, adenosine stimulates vasculogenesis and angiogenesis during wound healing and tumour growth. Currently, the clinical uses of adenosine are limited to treatment of supraventricular tachycardia or as a coronary vasodilator during radionuclide myocardial perfusion imaging. Due to the involvement of adenosine in various pathological conditions, the targeting of specific adenosine receptor (ADOR) subtypes in the vasculature using selective ADOR agonists or antagonists could have potential therapeutic benefit. However, the distribution of the receptors differs between species. Therefore, cross-species testing is essential to validate drug function.

Thiazolidinediones (TZDs) represent a class of peroxisome proliferator-activated receptor (PPAR)γ agonists widely used as insulin-sensitizers in the treatment of type 2 diabetes mellitus (T2DM). The beneficial effects of hypoglycemic drugs, including TZDs, on the hemostatic abnormalities associated to T2DM have been formerly related to improved metabolic control, rather than to direct effects. However, in recent years the pleiotropic effects of PPARγ agonists on hemostatic function have become evident. In particular, the role of platelets as a pivotal player in diabetes complications by stimulating and sustaining inflammation has been lately acknowledged. Upon activation platelets synthesize and release many bioactive substances such as thromboxane A2 (TXA2) or pro-inflammatory mediators including CD40 ligand (CD40L) that exert autocrine and paracrine activation processes in vascular inflammation leading to cardiovascular disease (CVD). Although PPARγ is a nuclear hormone receptor, anucleate platelets also highly express this receptor and treatment with synthetic PPARγ ligands dampens the release of soluble(s)CD40L and TXA2 in thrombin-activated platelets. Moreover, PPARγ through Sirtuin1 pathway has been implicated in modulating inflammatory and atherosclerotic processes in patients with T2DM. Therefore, in T2DM, where platelet activation contributes to the pathogenesis of CVD, TZDs may have an enhanced therapeutic role, despite some potentially serious adverse side effects. This review will discuss the pleiotropic effects of PPARγ treatment on the hemostatic abnormalities associated with T2DM, with particular focus on platelet activation.

We evaluated the effects of the glycosaminoglycan sulodexide (SDX; antithrombotic/profibrinolytic drug) on the activity and release of matrix metalloproteinases (MMPs) in human blood. This was a prospective non-randomized study, analyzing by zymography and ELISA the in vitro effects of SDX on pro-enzyme, complexed, and active MMP forms in plasma and serum from 60 healthy donors, and in U-937 leukemia cell line. The levels and zymographic profile of MMP-2 did not show significant changes among samples and during SDX treatments. However, pro- and complexed forms of MMP-9 were strongly affected by SDX treatment (P<0.001), with significant decrease of MMP-9 secretion from white blood cells in a dose-dependent fashion (P<0.0001), without any displacement of MMP prodomains. The mechanism of reduced release of MMP-9 forms from leukocytes and inhibition of proteolytic activity due to SDX treatment may support the hypothesis that drugs based upon inhibitors of MMP-9 activity may provide a therapeutic tool for the underlying pathological destruction of extracellular matrix, and offering novel pharmacologic applications for chronic inflammatory vascular diseases, including varicose vein and chronic venous diseases associated with enhanced MMP activation in blood and limbs.

Assessing the efficacy and safety profiles of new oral direct Factor Xa (FXa) inhibiting anticoagulants compared with low-molecular-weight heparins (LMWHs) in elective total hip and knee arthroplasty (THA and TKA). The literature review only searched for randomised-controlled trials (RCTs) published before September 2011. Five eligible THA RCTs with a total of 12,184 patients and 5 eligible TKA RCTs with a total of 13,169 patients were identified. Mantel- Haenszel random-effects model was used to create meta-analyses of pooled data for each surgical group. The primary efficacy outcome was the risk of venous thromboembolism (VTE) and all-cause mortality, and the primary safety outcome was the risk of major bleeding. The THA and TKA primary efficacy outcome meta-analyses calculated relative risks (RR) of 0.55 (95% confidence interval 0.32 to 0.94) and 0.68 (95% confidence interval 0.53 to 0.87), respectively in favor of the oral direct FXa inhibitors. The primary safety outcome meta-analyses for the THA and TKA surgical groups revealed an RR of 1.27 (95% confidence interval 0.56 to 2.86) and 0.94 (95% confidence interval 0.44 to 1.98), which shows no significant difference between oral FXa inhibitors and LMWHs. This review demonstrated that oral direct FXa inhibitors have a superior efficacy to LMWHs when used as thromboprophylaxis in both THA and TKA. The safety profile of these new oral anticoagulants was not significantly different to that of LMWHs.