Current Vascular Pharmacology - Volume 9, Issue 6, 2011

Aim: To assess the reduction in estimated cardiovascular disease (e-CVD) risk after multifactorial treatment for 6 months and follow this change during the next 3-years. Patients-Methods: This prospective, randomized, target driven study included 1,123 subjects (512/611 men/women, aged 45-65 years) with metabolic syndrome (MetS) without diabetes or CVD referred to specialist outpatient clinics. Patients were randomized to two treatment groups: group A with low density lipoprotein cholesterol (LDL-C) target of >100 mg/dl and group B with a target of <130 mg/dl. Atorvastatin was used in both groups on top of optimal multifactorial treatment, (quinapril, amlodipine, hydrochlorothiazide for hypertension, metformin for impaired fasting glucose, and orlistat for obesity). The e-CVD risk was calculated using the Framingham, the PROCAM and Reynold's equations. Results: Reductions in e-CVD risk at 6 months were >50%in all patients, but were superior in group A and in women. Reductions were even greater during the next 3-years and were mainly attributed to changes in lipid profile. Actual CVD events were 1 in group A and 13 in group B; p=0.0012. Conclusions: Attaining the treatment target of LDL-C<100 mg/dl within multifactorial treatment of MetS by expert clinics, is achievable and beneficial even in patients without diabetes or known CVD. This induces a considerable e-CVD risk reduction in MetS patients. Actual CVD events were negligible, suggesting that e-CVD risk overestimates actual CVD risk in MetS, at least in patients achieving LDL-C<100 mg/dl [ClinicalTrials.gov ID: NCT00416741].

Atherosclerotic critical limb ischemia (CLI) is manifested by ischemic rest pain, non-healing ulcers or gangrene. The incidence of CLI is estimated to be approximately 500-1000 new cases per year per million people and is expected to grow in developed countries as the population ages with an increasing prevalence of diabetes. Patients diagnosed with CLI are at very high risk of major amputation and cardiovascular morbidity and mortality and experience poor physical function and quality of life. The goals of treatment for CLI are relieving ischemic pain, healing ulcers, preventing limb loss, improving patient function and quality of life, and prolonging survival. Prompt surgical or endovascular revascularization is currently recommended for limb salvage in CLI. All patients with CLI should receive cardiovascular risk reduction therapies, focused on optimizing antiplatelet therapy and risk factor management, to reduce cardiovascular event rates. Adjunctive pharmacotherapy with antithrombotic drugs, statins, and beta-blockers is critical to decrease perioperative cardiovascular complications in patients undergoing surgical vascular reconstruction and enhance postrevascularization arterial and graft patency. In non-reconstructable patients with stable pain and tissue loss, evidence suggests that prostanoids, dedicated wound care programs, and several mechanical devices, such as spinal cord stimulation, intermittent pneumatic compression, and hyperbaric oxygen therapy, can alleviate ischemic symptoms and improve limb salvage. Current medical armamentarium used in treating ischemic wounds also includes ultrasound and negative pressure wound therapy. Therapeutic neovascularization, including gene- and cell-based approaches, is a novel promising tool in the management of CLI under ongoing investigation.

High-mobility group box-1 (HMGB1) is a nuclear protein that acts as a cytokine when released into the extracellular milieu by necrotic and inflammatory cells, and is involved in inflammatory responses and tissue repair. This protein is released passively during cellular necrosis by almost all cells that have a nucleus, but is also actively secreted by immune cells such as macrophages and monocytes. This cytokine plays a key role in mediating the local and systemic responses to several stimuli and might have therapeutic relevance. Indeed, vessel-associated stem cells, injected into the general circulation of dystrophic mice, migrate to sites of tissue damage in response to the HMGB1 signal, by a nuclear factor-κB-dependent mechanism. Moreover, endogenous HMGB1 enhances angiogenesis and restores cardiac function in a murine model of myocardial infarction, and the exogenous administration of HMGB1 after myocardial infarction leads to the recovery of left ventricular function through the regeneration of cardiomyocytes. Finally, recent findings show that endogenous HMGB1 is crucial for ischemia-induced angiogenesis in diabetic mice and that HMGB1 protein administration enhances collateral blood flow in the ischemic hind limbs of diabetic mice through a VEGF-dependent manner. The mechanisms of action of this protein are complex and are not well known or defined. The objective of this review is to evaluate the data regarding the tissue regeneration effects of HMGB1, with the aim of providing practical considerations about this topic for the management of subjects affected by ischemic and degenerative diseases.

Recent data from genetic and epidemiological studies strongly support a causal relationship between elevated lipoprotein(a) [Lp(a)] concentrations and the development of atherosclerosis and cardiovascular disease. This relationship is continuous, without an Lp(a) threshold, and it is independent of low density lipoprotein and high density lipoprotein cholesterol (LDL-C and HDL-C, respectively) levels. Although the mechanism(s) through which Lp(a) promotes atherosclerosis are not clearly understood, proposed mechanisms include an increased Lp(a)-associated cholesterol entrapment in the arterial intima, inflammatory cell recruitment, carrying of proinflammatory oxidized phospholipids, impairing fibrinolysis by inhibition of plasminogen activation and enhancing coagulation by inhibition of the tissue factor pathway inhibitor. Phenotypically there are two forms, isolated hyperlipoproteinemia(a) in the presence of normal LDL-C, and combined elevations of Lp(a) and LDL-C. There are no drugs or other therapeutic options available that selectively decrease Lp(a). Those that can lower Lp(a) levels only have a moderate effect and their actions include decreasing LDL-C levels. The strongest effects are seen with niacin at high doses. Nevertheless, there is no convincing evidence that decreasing isolated elevations of Lp(a) offers cardiovascular benefit. This review considers the evidence supporting the association between Lp(a) and atherosclerotic disease, discusses the potential mechanisms involved in the pro-atherosclerotic potential of Lp(a), and evaluates the therapeutic options that decrease elevated Lp(a) levels.

Venous thromboembolism is a common condition and low molecular weight heparins (LMWHs) are widely used for its treatment. Chronic kidney disease (CKD) is also a frequent disease especially in subjects with comorbidities admitted to internal medicine wards. LMWHs are eliminated by the kidney and their half-life is increased in renal impairment. Based on a series of available studies we analyzed the relationship between treatment with LMWHs and different degrees of renal impairment including end-stage renal disease (ESRD). In order to reduce haemorrhagic risk, the LMWH dose should be reduced in CKD, even if reducing LMWH dose could impair drug effectiveness. Further studies relating glomerular filtration rate to LMWH effectiveness and side effects are required.

Both elevated levels of uric acid and non-alcoholic fatty liver disease (NAFLD) have been associated with increased vascular risk. Furthermore, certain drugs (e.g. lipid and blood pressure lowering) that decrease)cardiovascular risk and improve/preserve renal function were shown to influence serum uric acid (SUA) levels and/or NAFLD. A link between hyperuricaemia and NAFLD has also been suggested. This review considers the associations between hyperuricaemia, NAFLD and vascular risk. We also discuss the effects of different drug treatments on SUA and NAFLD. As NAFLD is a very common condition, future work in this field is needed with regard to a more practical definitive diagnosis, evidence- based treatments and a better understanding of the possible links between NAFLD, elevated SUA levels, cardiovascular disease and chronic kidney disease. Whether treating hyperuricaemia and NAFLD will translate into a reduced risk of vascular events requires further investigation.

Polyamines are organic polycations expressed by all living organisms, which are known to play an essential role in cell proliferation and differentiation. Recent studies revealed their involvement also in cell contractility and migration and in programmed cell death. These processes are known to contribute to restenosis, a pathophysiological process occurring in 10-20% of patients submitted to revascularization procedures. The advent of bare metal stents and of drugeluting stents has significantly reduced but not eliminated the incidence of restenosis, which thus remains a clinically relevant problem. Despite the potential role of the polyamine pathway as a therapeutic target due to its involvement in proliferation, apoptosis and migration of vascular cells, experimental inhibition of polyamine synthesis and/or uptake has been poorly investigated in animal models of vascular disease. Here we review the current knowledge about molecular mechanisms related to polyamine functions, with particular reference to the role played by polyamines in vascular cell pathophysiology, together with experimental evidence obtained so far in animal models of (re)stenosis. We also evaluate the advantages of different routes of administration of polyamine synthesis/transport inhibitors and polyamine analogue molecules. Increasing knowledge about the molecular mechanisms and functions of polyamines is expected to shed new light on their potential role as a therapeutic target for restenosis reduction.

The majority of individuals with pre-diabetic states eventually appear to develop diabetes mellitus. During the pre-diabetic state, that may last many years, the risk of cardiovascular disease is modestly increased, with impaired glucose tolerance being slightly stronger predictor for future cardiovascular disease than impaired fasting glucose. The role of different antihypertensive drugs in the acceleration or the delay of diabetes onset is controversial. Agents that interrupt the renin-angiotensin system, such as angiotensin converting enzyme inhibitors and angiotensin receptor blockers are likely to be beneficial in the prevention of diabetes, while calcium channel blockers are thought to act metabolically neutral. In contrast, diuretics or β-blockers, and especially their combination, are thought to increase the incidence of diabetes. Carvedilol, a non-selective β-blocker with α1-blocking properties, and nebivolol, a third-generation highly selective β1- blocker with additional endothelial nitric oxide (NO)-mediated vasodilator activity have been shown to have a favorable effect on glucose metabolism compared with others β-blockers. Nevertheless, the key goal still remains to reduce blood pressure, which may require combination of different antihypertensive drug classes. Changes from diuretics and β- blockers to renin-angiotensin system inhibitors certainly have cost implications. However, treatment with angiotensin converting enzyme inhibitors and angiotensin receptor blockers may be cheaper in the long run, due to less risk of newonset diabetes and other metabolic disturbances. Thus, for patients with pre-diabetes it is wise to choose medications with the least diabetogenic potential and until more data are available, it seems prudent to restrict use of diuretics and classic β- blockers.

Ischemic stroke is the third most common cause of death and of long-term disability and exhibits a high recurrence rate. Therefore, appropriate primary and secondary prevention is mandatory. In non-cardioembolic stroke, in addition to lifestyle changes and to targeted treatments, current guidelines recommend antiplatelet treatment. In cardioembolic stroke, Vitamin K antagonists (VKAs) are recommended. Although a favorable risk/benefit ratio of both treatments has also been demonstrated in elderly patients, registry data emphasize that such interventions are often under-used, especially in patients with atrial fibrillation (AF). Furthermore, variability in the inter-individual response to drugs has been recognized as a leading cause of event recurrence. Thus, in addition to poor adherence, efficacy and safety issues appear to be involved in the recurrence rate of stroke. In this review, we report main Registries data on adherence to stroke prevention treatment schedule. We also discuss the major limitations of “traditional” antithrombotic drugs and report Phase III study results on safety and efficacy of new antiplatelet and anticoagulant drugs, with emphasis on stroke prevention.

In spite of enormous efforts, myocardial infarction is one of the most common causes of morbidity and mortality worldwide. The molecular mechanisms underlying the pathological myocardial alterations in affected patients are not fully elucidated. Recent studies have uncovered an important regulatory role for microRNAs (miRNAs), a family of small non-coding RNA molecules which - by translational repression or messenger RNA (mRNA) degradation - primarily act as negative regulators of gene expression. MiRNAs have been identified as regulatory key players during cellular differentiation, proliferation, and apoptosis. Recent work has unveiled an important impact of miRNAs on the pathophysiology of myocardial infarction and consecutive myocardial alterations, including arrhythmia, remodelling processes, cardiac fibrosis, and hypertrophia. Additionally, specific miRNAs have been identified to be either elevated or decreased in the blood plasma after myocardial infarction. Determination of miRNA expression levels therefore offers a potential prognostic and/or predictive value. Future therapeutic concepts aiming at attenuation of ischemia-induced harm and reduction of maladaptive changes may include strategies to influence altered miRNA expression patterns. In this review, we summarize current knowledge of the modulating role of miRNAs in pathological alterations occurring in myocardial infarction as well as currently available data concerning miRNAs as diagnostic markers and therapeutic targets.

Uremic subjects, in addition to accelerated atherosclerosis, develop diffuse media vascular calcification (VC) which, in turn, is associated with increased vascular stiffness and mortality risk. Two sets of risk factors for VC can be considered: passive deposition of calcium-phosphate and active transformation of vascular smooth muscle cells into osteoblastic- like cells. The former is linked with the metabolic imbalance in divalent ions that affects renal patients at any stage of the disease; the latter is secondary to a recently discovered mechanism of cellular trans-differentiation caused by deranged local concentration of divalent ions. Also, the role of inhibitors of calcification is under investigation. These include circulating or local, substances like fetuin, matrix GLA protein or osteoprotegerin. Their biologic importance is supported by the occurrence of calcification in transgenic animals lacking these factors. Accordingly, VC is a complex biologic and incompletely understood process that deserves further research, in order to develop specific therapeutic strategies. In general, once established, these calcifications are not considered to be reversible; therefore, prevention is the main treatment option. With this aim, in uremic patients it is now recommended to adopt restricted ranges of serum concentrations for calcium, phosphate and parathyroid hormone which are associated with a lower rate of calcification. To target these recommended ranges, new drugs, like selective vitamin D receptor activators, calcium sensing receptor modulators and calcium free intestinal phosphate binders, have been introduced. Moreover new possible pathogenetic pathways are considered (e.g. vitamin K deficiency). Further, in patients with calciphylaxis, the most severe form of VC, experimental therapies are suggested, with drugs like sodium thiosulphate or bisphosphonates. Drugs capable of reversing the process of trans-differentiation from osteoblast-like to vascular smooth muscle cells could be developed in the future.

Gestational diabetes mellitus (GDM) is a syndrome compromising the health of the mother and the fetus. Endothelial damage and reduced metabolism of the vasodilator adenosine occur and fetal hyperinsulinemia associated with deficient insulin response and a metabolic rather than mitogenic phenotype is characteristic of this pathology. These phenomena lead to endothelial dysfunction of the fetoplacental unit. Major databases were searched for the relevant literature in the field. Special attention was placed on publications related with diabetes and hormone/metabolic disorders. We aimed to summarize the information regarding insulin sensitivity changes in GDM and the role of adenosine in this phenomenon. Evidence supporting the possibility that fetal endothelial dysfunction involves a functional link between adenosine and insulin signaling in the fetal endothelium from GDM pregnancies is summarized. Since insulin acts via membrane receptors type A (preferentially associated with mitogenic responses) or type B (preferentially associated with metabolic responses), a differential activation of these receptors in this syndrome is proposed.

Anticoagulant therapy in patients with atrial fibrillation requires careful evaluation because its benefits i.e. prevention of thromboembolism, must be greater than the risk of bleeding. Patients at higher risk of thrombosis are evaluated through specific scores, such as the CHA2DS2VASc, coupled with scoring systems for assessing bleeding risks, such as the HAS-BLED score. In addition to bleeding, other risks have been associated with the use of warfarin, including an increased susceptibility to vascular calcifications and fractures caused by a reduction in the levels of vitamin K dependent carboxylated enzymes, matrix Gla-protein (MGP) and bone Gla-protein or osteocalcin (BGP). In fact, while on one side warfarin is used to prevent embolism, on the other hand acting as a vitamin K antagonist it blocks the inhibitory effect of MGP on vascular calcification. Similarly, patients treated with warfarin carry a greater risk of developing osteoporosis and fractures, due to reduced BGP activity. Recently, a new generation of anticoagulant drugs has been developed, such as dabigatran, a direct thrombin inhibitor, and rivaroxaban, a direct factor-Xa inhibitor. They offer an interesting alternative to warfarin, because they do not require frequent blood tests for monitoring while offering similar results in terms of efficacy. Lacking the inhibitory effect on the vitamin K cycle, the consequent side effects can be avoided. If, compared to warfarin treated patients, a lower incidence of vascular calcifications and fractures will be demonstrated, the advantages over warfarin may be even greater, leading to further benefits in terms of morbidity and mortality.